Charge-Enhanced Brønsted Acids: Catalyst Designs and ...

Charge-Enhanced Brønsted Acids: Catalyst Designs and Analytical

Methods

A DISSERTATION

SUBMITTED TO THE FACULTY OF THE

UNIVERSITY OF MINNESOTA

BY

Curtis Payne

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

Steven R. Kass, Adviser

June 2020

i

Acknowledgement

First, I want to thank Dr. Steven Kass for his patience, guidance, and support

throughout my entire graduate career. His knowledge and advice on research and all

aspects of being scientist will never be forgotten and will be carried with me in my future

career.

I want to thank all current and previous Kass group members that I encountered on

this journey. You provided a fun, easy-going, and supportive environment even when the

research was not so generous.

Thank you to Dr. Jane Wissinger for her guidance as an organic chemistry instructor

and hiring me as the Head Night TA. I will never forget the skills I have acquired from

governing over 30+ volunteers and TAs to ensure a successful semester of instructing

organic chemistry. I would also like to acknowledge Dr. Juntian Zhang and his dedication

as the Organic Head TA as you made my job easier with your efforts.

I want to thank everyone in the Chemistry Department for the great atmosphere and

fun opportunities that were available. A special recognition to Amy, Grant, Robin, Patrick,

Mary for their support and friendship. Additionally, I want to thank all of my friends outside

of the Chemistry Department for their understanding and support.

Thank you to my parents, sisters, brother, and nieces for their love and support during

my journey. Lastly and most importantly, thank you to Dr. Taylor Hutchins for being here

for all the highs and lows during this process. I would have not been able to accomplish

this feat without your love and support.

ii

Abstract

Hydrogen bonding is a crucial interaction in Nature and plays an important role in the

structure and stability of DNA, ion molecular recognition, and the reactivity of enzymes. In

the last few decades, synthetic chemists have investigated hydrogen bond donors in the

development of metal-free catalysts for a variety of reactions. In these studies, a more

acidic species generally results in improved reactivity and stereoselectivity, and a recent

investigation uncovered that the acidity of a compound in nonpolar media correlates with

its gas phase acidity better than its pKa value in DMSO. As a result, charged hydrogen

bond donors and Brønsted acids have been synthesized and are more effective catalysts

in nonpolar media compared to their neutral analogues. In this dissertation, this charge-

enhanced effect is examined through a structure-reactivity relationship and new

organocatalytic designs are explored. Additionally, improved analytical methods for the

characterization and investigation of these cationic Brønsted acids are discussed.

iii

Table of Contents

List of Tables.....................................................................................................................vii

List of Figures.....................................................................................................................x

List of Schemes...............................................................................................................xiv

List of Abbreviations.......................................................................................................xviii

Chapter 1: Background and Introduction.......................................................................1

1.1 Hydrogen Bonds...........................................................................................................1

1.2 Hydrogen Bonding in Catalysis.....................................................................................2

1.2.1 Nature.................................................................................................................2

1.2.2 Organocatalysis..................................................................................................3

1.3 Brønsted Acid Organocatalysis....................................................................................4

1.4 Various Brønsted Acid Organocatalysts.......................................................................7

1.4.1 Ureas/Thioureas..................................................................................................8

1.4.2 BINOL...............................................................................................................18

1.5 Design Strategies for Enhanced Brønsted Acid Organocatalysts...............................27

1.6 Acidity in Nonpolar Solvents.......................................................................................28

1.6.1 UV-Vis Spectroscopic Titration..........................................................................29

1.6.2 31P NMR Titration Method..................................................................................30

1.6.3 IR Spectroscopy................................................................................................31

1.7 Charge-Enhanced Brønsted Acid Catalysts...............................................................34

1.7.1 Charge-Enhanced Thioureas............................................................................34

1.7.2 Charge-Enhanced Phosphoric Acids.................................................................36

1.8 Thesis Focus..............................................................................................................39

iv

Chapter 2: Structural Considerations for Charge-Enhanced Brønsted Acid

Catalysts.........................................................................................................................40

2.1 Introduction................................................................................................................40

2.2 Results and Discussion..............................................................................................43

2.3 Conclusions...............................................................................................................55

2.4 Experimental..............................................................................................................57

Chapter 3: How Reliable Are Enantiomeric Excess Measurements Obtained by

Chiral HPLC?..................................................................................................................71

3.1 Introduction................................................................................................................71

3.2 Results and Discussion..............................................................................................72

3.3 Conclusions...............................................................................................................85

3.4 Experimental..............................................................................................................88

Chapter 4: Expanding the Reaction Scope of a Chiral Charge-Enhanced Thiourea

and Improving its Reactivity and Selectivity With a Brønsted Acid Cocatalyst......90

4.1 Introduction................................................................................................................90

4.2 Results and Discussion.............................................................................................93

4.3 Conclusions and Future Work.................................................................................106

4.4 Experimental............................................................................................................107

v

Chapter 5: Investigation of a Computationally Designed Thiourea for Improved

Catalytic Performance.................................................................................................111

5.1 Introduction..............................................................................................................111

5.2 Results and Discussion............................................................................................114

5.3 Conclusions/Outlook................................................................................................123

5.4 Experimental............................................................................................................124

Chapter 6: Electrostatically-Enhanced BINOL Hydrogen Bonding Catalysts.......138

6.1 Introduction..............................................................................................................138

6.2 Results and Discussion............................................................................................140

6.3 Future Work/Outlook................................................................................................146

6.4 Experimental............................................................................................................149

Bibliography.................................................................................................................160

Chapter 1.......................................................................................................................160

Chapter 2.......................................................................................................................174

Chapter 3.......................................................................................................................182

Chapter 4.......................................................................................................................187

Chapter 5.......................................................................................................................191

Chapter 6.......................................................................................................................196

vi

Appendices..................................................................................................................201

Appendix for Chapter 2...................................................................................................201





vii

List of Tables

Table 1.1. General Bond Lengths and Strengths of the Major Types of Hydrogen Bonds...2

Table 1.2. Asymmetric Morita-Baylis-Hillman Reactions Catalyzed by BINOL and H8-

BINOL Hydrogen Bonding Catalysts………….………………….……………..………..23

Table 1.3. An Enamine Mannich Reaction Catalyzed by BINOL and Catalyzed by BINOL

and H8-BINOL Hydrogen Bonding Catalysts……..……………………………......…....24

Table 1.4. N-Nitroso Aldol/Michael Addition Catalyzed by BINOL Derivatives…...………26

Table 1.5. Comparison of Acidity and Reactivity in a Diels-Alder Cycloaddition………….28

Table 1.6. Comparison of pKa values, gas-phase acidities, and hydroxyl frequency shifts

(Δʋ) of Charged and Neutral Phenols……….……………………………………………32

Table 1.7. A Diels-Alder Cycloaddition Catalyzed by Various Achiral Phosphoric Acids...36

Table 1.8. Asymmetric Friedel-Crafts Reaction Catalyzed by BINOL-based Phosphoric

Acids………….……………………………………………………………...……………...38

Table 2.1. IR O-H and N-H Stretching Frequencies and Gas-Phase Acidities of a Series

of Phenol and Pyridinium Derivatives…………………………………………………….45

Table 2.2. Wavelength Shifts and Binding Constants from UV-vis Titrations with 2.1……51

Table 2.3. Kinetic Data for a Friedel-Crafts Reaction between N-Methylindole and trans-

β-Nitrostyrene............................................................................................................53

Table 3.1. Data collected at 220 nm under the most favorable separation conditions (1%

overlap) where the major (R) enantiomer eluted first..................................................76

Table 3.2. Data Collected at 220 nm Under Less Favorable Separation Conditions (4%

Overlap) Where the Major (R) Enantiomer Eluted First...............................................77

viii

Table 3.3. Observed results at 220 nm under the most favorable separation conditions

(1% overlap) where the major (S) enantiomer eluted second......................................78

Table 3.4. Observed results at 220 nm under the less favorable separation conditions (4%

overlap) where the major (S) enantiomer eluted second.............................................79

Table 3.5. Data collected at 220 nm under conditions leading to 17% peak overlap in a

racemic mixture where the major (R) enantiomer was first off the column...................82

Table 3.6. Data collected at 220 nm under conditions leading to 17% peak overlap in a

racemic mixture where the major (S) enantiomer eluted second off the column..........83

Table 3.7. General enantiomeric excess measurement guide for chiral HPLC.................87

Table 4.1. Attempts to Replicate the Results Obtained by Fan.........................................94

Table 4.2. Effect of Acid Additives in CDCl3......................................................................95

Table 4.3. Effect of Acid Additives in CD2Cl2...................................................................97

Table 4.4. Temperature Effects in CD2Cl2........................................................................99

Table 4.5. Screen of Thiourea Catalysts for an Oxa-Pictet-Spengler Reaction.............101

Table 4.6. Screen of Cocatalysts for an Oxa-Pictet-Spengler Reaction........................102

Table 4.7. Temperature Screen for an Oxa-Pictet-Spengler Reaction..........................104

Table 4.8. Preliminary Results for a Michael Addition Reaction Catalyzed by a Charged

Thiourea...................................................................................................................105

Table 5.1. Calculated Free Energies of Activation Leading to Each Product Enantiomer

Catalyzed by Substituted cis-1-Amino-2-indanol Thioureas.....................................113

Table 5.2. Results from the Friedel-Crafts Reaction between Indole and trans-β-

Nitrostyrene Catalyzed by Charged Thioureas.........................................................121

ix


Nitrostyrene Catalyzed by Neutral Thioureas...........................................................122

Table 6.1. Asymmetric Friedel-Crafts Reaction Catalyzed by Charged BINOLs............146

x

List of Figures

Figure 1.1. Hydrogen bonding between the base pairs of DNA..........................................1

Figure 1.2. Aldol reaction catalyzed by Type II aldolases via multiple hydrogen bonds......2

Figure 1.3. Comparison of Brønsted acid and Lewis acid metal-centered catalysis...........5

Figure 1.4. Common hydrogen bonding and strong acid catalysts.....................................5

Figure 1.5. Modes of activation by general and specific acid catalysis...............................6

Figure 1.6. Activation modes for single and double hydrogen bonding catalysts and for

strong acid catalysts (R* = chiral substituent)...............................................................7

Figure 1.7. Catalytic interactions by ureas and thioureas with two hydrogen bonds...........9

Figure 1.8. Generic interaction found by Etter et al. between substituted ureas and a

carbonyl group.............................................................................................................9

Figure 1.9. Intramolecular interaction between the ortho-hydrogens and sulfur atom in

thiourea 1.18 as it activates α,β-unsaturated ketone 1.14...........................................11

Figure 1.10. Thioureas bearing one or two chiral scaffolds..............................................12

Figure 1.11. Generic activation mode by a chiral, bifunctional thiourea............................12

Figure 1.12. Variations of Takemoto’s catalysts..............................................................14

Figure 1.13. Interactions between thiourea 1.19 and two substrates undergoing a Michael

addition......................................................................................................................15

Figure 1.14. Transition states proposed for the Friedel-Crafts alkylation between 1.23 and

1.24 facilitated by thiourea 1.22..................................................................................16

Figure 1.15. Self-aggregation of ureas and thioureas......................................................17

xi

Figure 1.16. Internal strategies to prevent urea/thiourea self-aggregation and improve

catalytic reactivity.......................................................................................................17

Figure 1.17. External strategies to prevent urea/thiourea self-aggregation and improve

catalytic reactivity.......................................................................................................18

Figure 1.18. Popular chiral diols for hydrogen bonding catalysis......................................19

Figure 1.19. Rotational hinderance positions in BINOL....................................................19

Figure 1.20. IR spectra of phenol in CCl4 in the absence (blue) and presence (red) of d3-

acetonitrile..................................................................................................................31

Figure 1.21. BINOL-based phosphoric acids bearing phosphonium ion, triphenylsilyl, and

TRIP substituents in the 3- and 3’-positions................................................................37

Figure 2.1. Charged catalysts screened in this work........................................................43

Figure 2.2. Changes in the N–H (open circles) and O–H (filled circles) IR frequencies of

pyridinium BArF4– salts in CD2Cl2 upon addition of CD3CN versus the corresponding

gas-phase G4 acidities of the free ions. Linear least squares fits provide the following

equations: Δʋ (cm–1) = -14.7 x ΔG°acid + 3451, r2 = 0.991 (N–H acids) and Δʋ (cm–1)

= -6.87 x ΔG°acid + 1939, r2 = 0.662 (O–H acids with 2.4H omitted and not shown)...47

Figure 2.3. UV-vis spectra from 300 to 600 nm for the titration of 2.1 with 2.3H. For clarity

only half of the spectra are shown and they correspond to the addition of 0.00, 0.35,

0.69, 1.02, 1.67, 2.89, 5.59, and 10.7 equivalents of 2.3H..........................................48

Figure 2.4. UV-vis spectra from 300 to 600 nm for the titration of 2.2Me with 2.1. For clarity

only half of the spectra are shown and they correspond to the addition of 0.00, 0.22,

0.44, 0.65, 0.76, 1.00, 1.50, 2.50, 5.80, 11.0, and 22.0 equivalents of 2.2Me..............49

xii

Figure 2.5. Linear least squares fit of the logarithms of the 1:1 equilibrium association

constants between 2.1 and the pyridinium salts listed in Table 2.2 versus the G4

acidities of the pyridinium ions. The equation for the line is ln K = -0.118 x ΔG˚acid +

37.2, r2 = 0.882, and the values for 2.2H and 2.2Me (open circles) were omitted from

the regression............................................................................................................52

Figure 2.6. Logarithm of experimental rate constants vs computed G4 gas-phase

acidities. A linear least squares fit using all 9 catalysts in Table 2.3 gives ln k = –0.126

x ΔG˚acid + 28.6, r2 = 0.875 whereas omission of 2.6 leads to ln k = –0.131 x ΔG˚acid +

29.9, r2 = 0.912 (not shown). Circles, diamonds, and triangles are used for 2.2Me–

2.4Me (O–H acids), 2.2H–2.4H, 2.5H, and 2.6 (N–H acids), and 2.5Me (C–H acids),

respectively................................................................................................................55

Figure 3.1. Chiral HPLC separations of 3.1 with 90:10 (solid line, 1% overlap) and

82.5:17.5 (dashed line, 4% overlap) hexanes/i-PrOH mixtures and 0.4% v/v NH4OAc

on a Whelk-O1 column...............................................................................................73

Figure 3.2. UV-vis spectrum of ibuprofen from 210-300 nm obtained with a HPLC-

photodiode array detector. Open circles are at the seven wavelengths used to monitor

all of the chiral separations.........................................................................................74

Figure 3.3. Calculated versus observed ees (%) at 220 nm with 4% overlap in a racemic

mixture. Filled circles and open triangles are for when the major enantiomer elutes first

and second, respectively; in the latter case the data have been offset by 1.0% along

the y-axis for clarity. Uncertainties are given by 2σ and are based on five

measurements (solid lines), whereas dotted lines were used for at least one of the

possible combinations using only three of the data points...........................................80

Figure 3.4. Separation of a racemic mixture of ibuprofen with a 72.5:27.5 hexanes/i-PrOH

mixture containing 0.4% v/v NH4OAc on a Whelk-O1 column as monitored at 220

nm..............................................................................................................................81

xiii

Figure 3.5. HPLC chromatographs of a 95 (R) : 5 (S) mixture monitored at 220 (top) and

254 nm (bottom) using favorable separation conditions (i.e., 1% overlap in a racemic

mixture)......................................................................................................................84

Figure 3.6. A comparison of the measured uncertainty in the ee (2σ) versus the

chromatogram resolution (Rs). Triangles, squares, and circles represent the 17, 4, and

1% data, respectively. Filled and unfilled symbols are for when major enantiomer

elutes off the column first and second, respectively....................................................85

Figure 4.1. Internal (a) and external (b) strategies to prevent thio(urea) aggregation.......91

Figure 4.2. Schreiner’s thiourea and its hydrogen bonding interactions...........................92

Figure 4.3. Thiourea catalysts screened in this work........................................................93

Figure 5.1. A thiourea bearing the cis-1-amino-2-indanol framework.............................111

Figure 5.2. The general mode of activation of thioureas 5.2 where R = H, CN, or t-Bu....112

Figure 6.1. Generic charge-enhanced BINOL catalysts.................................................140

xiv

List of Schemes

Scheme 1.1. Generic synthesis of ureas and thioureas.....................................................8

Scheme 1.2. A Claisen rearrangement catalyzed by urea 1.13........................................10

Scheme 1.3. A Diels-Alder cycloaddition catalyzed by various thioureas.........................11

Scheme 1.4. Asymmetric Strecker reaction catalyzed by a Jacobsen thiourea................13

Scheme 1.5. Enantioselective Michael reaction catalyzed by thiourea 1.19.....................14

Scheme 1.6. A Friedel-Crafts alkylation between 1.23 and 1.24 catalyzed by thiourea

1.22............................................................................................................................15

Scheme 1.7. Bromination of the 6,6’-poisitions of BINOL.................................................20

Scheme 1.8. Synthesis of H8-BINOL by hydrogenation of BINOL...................................20

Scheme 1.9. Generic route to 3,3’-substituted BINOLs....................................................20

Scheme 1.10. Synthesis of BINOL-based phosphoric acids...........................................21

Scheme 1.11. A Bayliss-Hillman reaction catalyzed by BINOL........................................21

Scheme 1.12. Proposed mechanistic pathways for the illustrated transformation............25

Scheme 1.13. UV-vis sensor 1.48 and its bound complex with a Brønsted acid (HX).......29

Scheme 1.14. Quantification of hydrogen-donating ability by observing the change in the

31P NMR chemical shift of phosphine oxides (1.50) and their bound complexes with

Brønsted acids (HX)...................................................................................................30

Scheme 1.15. Reactivities of neutral and charged phenol derivatives in a Friedel-Crafts

alkylation....................................................................................................................33

Scheme 1.16. A Friedel-Crafts alkylation catalyzed by neutral and charged thioureas.....35

xv

Scheme 1.17. An asymmetric Friedel-Crafts reaction catalyzed by thiourea 1.58............35

Scheme 1.18. An asymmetric Friedel-Crafts reaction catalyzed by BINOL-based

phosphoric acids........................................................................................................39

Scheme 2.1. UV-vis sensor 2.1 and its bound complex with a Brønsted acid...................41

Scheme 2.2. Synthetic routes for all three isomeric N-methylhydroxypyridinium BArF4

salts............................................................................................................................44

Scheme 2.3. Proposed binding modes for Brønsted acids such as 2.2Me with 2.1..........50

Scheme 2.4. Synthesis of control compound 2.6.............................................................54

Scheme 4.1. An asymmetric Friedel-Crafts reaction catalyzed by charged chiral thiourea

4.2..............................................................................................................................93

Scheme 4.2. An oxa-Pictet-Spengler reaction catalyzed by thioureas and a protonated

indoline cocatalyst....................................................................................................100

Scheme 4.3. Attempted asymmetric Friedel-Crafts alkylation........................................105

Scheme 4.4. An asymmetric 1,4-addition of N,N-dialkylhydrazones to β,γ-unsaturated α-

ketoesters catalyzed by thiourea 4.5........................................................................106

Scheme 5.1. An asymmetric Friedel-Crafts alkylation catalyzed by charged thiourea

5.1............................................................................................................................111

Scheme 5.2. Retrosynthetic analysis of the target thiourea catalyst 5.3.........................114

Scheme 5.3. Reagents and corresponding conversions of 1,2-additions into ketone

5.9............................................................................................................................114

Scheme 5.4. Synthesis of carbamate intermediates 5.12 and 5.14................................115

Scheme 5.5. A copper-catalyzed benzylic amidation that resulted in alkene 5.16 and

sulfamide 5.17..........................................................................................................116

xvi

Scheme 5.6. A rhodium-catalyzed amidation and the observed distribution of products

5.15 and 5.18...........................................................................................................117

Scheme 5.7. The enantiomers of 5.15 and its hydrolysis to afford amino alcohol 5.19..118

Scheme 5.8. Synthetic route of enantiopure 2-tert-butyl-cis-1-amino-2-indanol 5.5.......118

Scheme 5.9. Synthesis and absolute stereochemistry of thiourea salt (1S,2S)-5.20......119

Scheme 5.10. Final transformations to afford mono-charged thiourea catalyst 5.3........120

Scheme 5.11. Synthesis of 3,5-bis(trifluoromethyl)-phenyl variant 5.22.........................120

Scheme 5.12. A 1,4-addition between a β-keto ester and an α,β-unsaturated carbonyl and

a proposed transition state facilitated by thiourea 5.3...............................................124

Scheme 6.1. BINOL derivatives.....................................................................................139

Scheme 6.2. Synthesis of diiodo-intermediate 6.6.........................................................141

Scheme 6.3. Cross coupling reactions to synthesize 3,3’-di(3-pyridyl) and 3,3’-di(2pyridyl)

BINOLs....................................................................................................................142

Scheme 6.4. Synthesis of 3,3’-di(N-alkyl-3-pyridinium)-BINOLs....................................142

Scheme 6.5. Attempts to alkylate BINOL 6.10 and a proposed intramolecular interaction

that prevents this type of transformation...................................................................143

Scheme 6.6. Potential routes to synthesize iodide salt 6.18...........................................144

Scheme 6.7. Initial attempt at the synthesis of BINOL 6.21............................................144

Scheme 6.8. Progress towards protonated BINOLs 6.21 and 6.24................................145

Scheme. 6.9. Synthesis of phosphonium ion-tagged BINOL catalysts...........................147

Scheme 6.10. Asymmetric Morita-Baylis-Hillman reactions catalyzed by BINOL hydrogen

bonding catalysts.....................................................................................................148

xvii

Scheme 6.11. N-Nitroso aldol/Michael addition catalyzed by BINOL derivatives...........148

Scheme 6.12. A hetero-Diels Alder cycloaddition catalyzed by TADDOLs.....................149

xviii

List of Abbreviations

(g) - gas or gaseous

µL - microliter

µm - micrometer

µmol - micromole

Å - angstrom

AcCl - acetyl chloride

ACN - acetonitrile

Ar - aryl

ATR - attenuated total reflectance

BArF4 - tetrakis (3,5-bis(trifluoromethyl)phenyl)borate

BINOL - 1,1’-bi-2-naphthol

calc - calculated

cat. - catalyst

cm-1 - wavenumber

conv. - conversion

d - day

DCE - 1,2-dichloroethane

DDQ - 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DFT - density functional theory

DME - 1,2-dimethoxyethane

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

DNA - deoxyribonucleic acid

DPP - diphenyl phosphate

ee - enantiomeric excess

equiv. - equivalents

er - enantiomeric ratio

Et - ethyl

Et2O - diethyl ether

EtOH - ethanol

F - flow rate

xix

FT - Fourier transform

g - gram

G4 - Gaussian-4

Glu - glutamic acid or glutamate

h - hours

H-Bond - hydrogen bond

HPLC - high performance liquid chromatography

HRMS-ESI - high resolution mass spectrometry – electrospray ionization

Hz - hertz

i-Pr - isopropyl

IR - infrared

kcal mol-1 - kilocalorie per mole

LUMO - lowest unoccupied molecular orbital

mAU - milli-absorbance unit

Me - methyl

MeOH - methanol

mg - milligram

MHz - megahertz

min - minute

mL - milliliter

mM - millimolar

mm - millimeter

mmol - millimole

mol% - mole percent

mp - melting point

MPLC - medium pressure liquid chromatography

MS - molecular sieves

nm - nanometer

NMR - nuclear magnetic resonance

obs - observed

OTf- - triflate anion

PCM - polarizable continuum model

xx

Ph - phenyl

ppm - parts per million

PTFE - polytetrafluoroethylene

p-TsOH - para-toluenesulfonic acid

rac or (±) - racemic

Rs - resolution

rt - room temperature

s - second

s - slope sensitivity or peak threshold

T or temp - temperature

t1/2 - half-life

TADDOL - α,α,α’,α’-tetraaryl-1,3-dioxolan-4,5-dimethanol

TBS - tert-butyldimethylsilyl

t-Bu - tert-butyl

Tf2N- - bis(trifluoromethane)sulfonimide anion

Tf2NH - bis(trifluoromethane)sulfonimide or bistriflimide

TFA - trifluoroacetic acid

TFAA - trifluoroacetic anhydride

THF - tetrahydrofuran

TLC - thin layer chromatography

TOF - time of flight

TRIP - 2,4,6-triisopropylphenyl

Tyr - tyrosine

UV - ultraviolet

v/v – volume/volume

vis - visible

α - separation factor or selectivity factor

δ - chemical shift in ppm

ΔG°acid - gas phase acidity

Δʋ - change in IR frequency

1

Chapter 1: Background and Introduction

1.1 Hydrogen Bonds

Hydrogen bonds are key interactions found in various systems in Nature, such as the

base pairing within DNA (Figure 1.1) and the higher order aggregation and folding of

proteins. The unique properties of water and ice are a result of a large hydrogen bonded

network of individual water molecules.1,2

Figure 1.1. Hydrogen bonding between the base pairs of DNA.

A hydrogen bond (H-bond) is a noncovalent, electrostatic interaction between two

molecules or functional groups that can be generically represented as A-H···B.1,3 The

hydrogen bond donor (A-H) is a compound that is covalently bonded to the proton with an

electronegative atom (typically, A = oxygen, nitrogen, or sulfur), leading to a buildup of

positive charge on the hydrogen atom. The hydrogen bond acceptor (B) contains a lone

pair of electrons and is attracted to the positive end of the A-H dipole, forming a favorable

bridging interaction between the donor and acceptor.

Hydrogen bonds can be classified as weak, moderate, or strong interactions that span

from 0.5 to 40 kcal mol-1 (Table 1.1).4,5 This range of bond strengths has been shown to

correlate with the distance between the two interacting atoms (A and B). That is, a longer

bond results in a weaker interaction between bridging molecules.

2

Table 1.1. General Bond Lengths and Strengths of the Major Types of Hydrogen

Bonds.

Since protons are significantly smaller relative to other atoms, the donor and acceptor

can approach one another closely, forming strong hydrogen bonds.2 These strong

interactions come in two modes that describe the motion of the hydrogen atom between

the interacting atoms (A and B): a low-barrier hydrogen bond where the hydrogen atom

moves freely between A and B, and a single-well hydrogen bond where the hydrogen atom

is located at the midpoint of the donor and acceptor.2

The capability of the hydrogen bond to coordinate molecules together plays a key role

in the development of supramolecular structures,6 enables molecular recognition,7

influences crystal packing,8,9 and can be exploited to facilitate chemical reactions.1,4,10

1.2 Hydrogen Bonding in Catalysis

1.2.1 Nature

Enzymes accelerate chemical reactions by forming hydrogen bonds with substrates,

thereby stabilizing reactive intermediates and lowering barriers of activation.11,12 The

active sites of these catalysts have evolved over long periods of time, leading to very

specific molecular recognition. As a result, extremely efficient and selective chemical

transformations are achieved.12 For example, Type II aldolases13,14 utilize multiple

hydrogen bonds to activate carbonyls for nucleophilic attack (Figure 1.2).15

Type H-bond length (Å)a H-bond strength (kcal mol-1)

Weak > 3.2 < 4

Moderate 2.5 – 3.2 4 – 15

Strong 2.2 – 2.5 15 – 40

aDistance between atoms A and B in the interaction of A-H···B.

3

Figure 1.2. Aldol reaction catalyzed by Type II aldolases via multiple hydrogen bonds.

1.2.2 Organocatalysis

Since the 1970s, the power and efficiency of enzymes have inspired synthetic

chemists to investigate small, metal-free molecules as catalysts, known as

organocatalysts.16,17 This area of research has been described by Breslow as “biomimetic

chemistry,”18 which encompasses the efforts to design small organic molecules that

imitate biological enzymes. Thus, organocatalysts can be viewed as artificial enzymes19

that have advantages over the macromolecules that they are designed from. For example,

they are typically more stable, less expensive, and can function under conditions that are

unsuitable for enzymes.20,21

Since organocatalysts are purely organic molecules,17 they exhibit desired qualities

that are absent in metal-centered complexes. That is, organocatalysts typically require

milder reaction conditions (i.e., lower temperatures and/or pressures), are less toxic and

better for the environment, and are more stable in air and water than their inorganic

4

analogues.22 Overall, organocatalysts are viewed as greener alternatives to metal-

centered catalysts.

In the early years of organocatalysis, catalyst loadings were typically 30-40 mol%,23

whereas metal complexes are commonly utilized on much smaller scale and have even

been effective at ppm levels.24,25 Thus, developing more reactive compounds is a major

focus in organocatalysis. Today, typical catalyst loadings range from 0.5 to 20 mol% with

10-20 mol% being most common.23 From an industrial perspective, this range is still too

high and more efficient catalysts are required to achieve a target of ≤ 0.1 mol%.26

Organocatalysis has only blossomed in the last 40-50 years and consequently is

underdeveloped compared to biocatalysis and metal-centered catalysis. However, the

field is still considered a major pillar in enantioselective synthesis alongside enzymatic

and inorganic-mediated catalysis.15,21,23 Within the realm of organocatalysis, metal-free

Lewis acids,27 Lewis bases,28,29 and Brønsted bases30 have been explored,17 but only

Brønsted acid organocatalysts will be discussed in detail in this dissertation.

1.3 Brønsted Acid Organocatalysis

The simplest definition of a Brønsted acid is a compound that donates a proton, either

partially through a hydrogen bond or fully to a given substrate. These interactions are

involved in a variety of mechanisms to promote chemical transformations.31 Analogous to

Lewis acid metal-centered catalysis, the most common pathway lowers the energy of the

lowest unoccupied molecular orbital (LUMO) of a substrate, activating the reagent toward

nucleophilic attack (Figure 1.3).32

5

Figure 1.3. Comparison of Brønsted acid and Lewis acid metal-centered catalysis.

Brønsted acid catalysts are generally sorted into two subgroups based on their relative

acidities: hydrogen bonding catalysts and strong acid catalysts (Figure 1.4). The former

class describes compounds with weaker acidities such as phenols (1.1), ureas (1.2) and

thioureas (1.3), squaramides (1.4), and diols such as α,α,α’,α’-tetraaryl-1,3-dioxolan-4,5-

dimethanol (TADDOL, 1.5) and 1,1’-bi-2-naphthol (BINOL, 1.6). The latter category

includes more acidic catalysts such as phosphoric acids (1.7), phosphoramides (1.8), and

carboxylic acids (1.9).33,34

Figure 1.4. Common hydrogen bonding and strong acid catalysts.

6

Hydrogen bonding catalysts operate through general Brønsted acid catalysis, where

complete or partial protonation occurs in the rate-determining step of the mechanism

(Figure 1.5a).23 Stronger acids, however, facilitate reactions through a reversible

protonation that occurs prior to the rate determining step, referred to as specific Brønsted

acid catalysis (Figure 1.5b).23 It should be noted that in most cases the distinction between

these pathways is not very clear.17 That is, if the reaction conditions diminish the catalyst

acidity or if the substrate is a weak Brønsted base, then stronger acids can also operate

through the general acid catalysis model.35

Figure 1.5. Modes of activation by general and specific acid catalysis.

For hydrogen bonding organocatalysts, the number of active hydrogen bonds plays a

role in their activation mode of substrates (Figure 1.6). That is, single, double, or multiple

(>2) hydrogen bond donors feature different binding pockets that lead to different

reactivities and selectivities. Double hydrogen bond donors have been shown to be more

efficient than single donors since two hydrogen bonds increase the strength and

directionality of the interaction between the catalyst and substrate.15,32 Due to these

advantages, double hydrogen bond donors can activate a variety of molecules including

aldehydes, ketones, esters, several imine derivatives, and nitro compounds more

7

effectively than single hydrogen bond donors.15 When an asymmetric hydrogen bond

donor is employed, stereoselectivity is introduced in the transition state due to the

influence of the chiral catalyst.32

In contrast, a strong Brønsted acid protonates the substrate and due to electrostatic

attraction, the conjugate base of the catalyst remains coordinated to the activated

substrate during the reaction as a contact ion pair (Figure 1.6).33,34 When a chiral

organocatalyst is employed, the observed stereoselectivity in the product is a result of this

ionic interaction.

Figure 1.6. Activation modes for single and double hydrogen bonding catalysts and for

strong acid catalysts (R* = chiral substituent).

1.4 Various Brønsted Acid Organocatalysts

Over the past 40-50 years, a variety of hydrogen bonding catalysts36 have been

studied including silanediols,37–39 ureas and thioureas,40 squaramides,41 and TADDOLs,42–

44 as well as cationic species such as amidinium45 and guanidinium46,47 ions.48 Research

on stronger acids has focused on phosphoric acids,33,34 carboxylic acids,49 and

phosphoramides.50,51 In the following sections, (thio)ureas and 1,1’-bi-2-naphthols

(BINOLs) will be discussed in greater detail.

8

1.4.1 Ureas/Thioureas

Ureas (1.2) and thioureas (1.3) have received significant attention as double hydrogen

bond donors despite their relatively weak acidities.52 These compounds are most

commonly synthesized in one step (Scheme 1.1) from a primary amine (1.10) and an

isocyanate (1.11, for ureas) or an isothiocyanate (1.12, for thioureas). Due to the simple

construction of this functional group, many achiral and chiral derivatives have been

developed and their reactivities and selectivities have been observed for a variety of

chemical transformations.53

Scheme 1.1. Generic synthesis of ureas and thioureas.

Urea and thioureas have been shown to facilitate reactions by three different

mechanisms.54,55 The double hydrogen bond donor can directly bind to the substrate

(Figure 1.7a), or the acid catalyst can chelate an anion and promote a chemical reaction

through a substrate-catalyst ion pair (Figure 1.7b).56 A special case of this latter pathway

is known as anion abstraction (Figure 1.7c),55 where the (thio)urea removes an anionic

leaving group of a substrate, forming a reactive carbenium intermediate that is then

trapped by a nucleophile.

9

Figure 1.7. Catalytic interactions by ureas and thioureas with two hydrogen bonds.

The hydrogen bond donating abilities of ureas were recognized in the 1990s by Etter

et al., where co-crystals of ureas and a variety of Lewis bases (ketones, ethers, epoxides,

alcohols, and anilines) were formed (Figure 1.8).57

Figure 1.8. Generic interaction found by Etter et al. between substituted ureas and a

carbonyl group.

Inspired by this work, Curran et al. explored ureas as hydrogen bonding catalysts.58,59

Urea 1.13 was shown to accelerate a Claisen Rearrangement by over an order of

magnitude when a stoichiometric amount was employed compared to the background rate

(Scheme 1.2).59

10

Scheme 1.2. A Claisen rearrangement catalyzed by urea 1.13.

Urea self-association,60 where intermolecular hydrogen bonds form between the N-H

group and an adjacent urea carbonyl, has limited the catalytic activity of these compounds.

The lower electronegativity of sulfur compared to oxygen makes self-association and

hydrogen bonding with solvent molecules at the heteroatom less favorable.61 Thioureas

are also more acidic than ureas (pKa = 21.1 and 26.9, respectively in DMSO for the parent

compounds).62 Thus, thioureas are less prone to aggregation and form stronger

interactions with substrates than their urea counterparts.63

Schreiner and Wittkopp synthesized various thiourea derivatives and compared their

reactivities in a Diels-Alder cycloaddition between methyl vinyl ketone (1.14, Scheme 1.3)

and cyclopentadiene (1.15).64 A common trend was observed, where aromatic

substituents with meta- and para-electron withdrawing groups led to more active catalysts

(1.16 < 1.17 < 1.18) due to increased acidity of the N-H bonds.

equiv. of 1.13 krel

0.0 1.0 0.1 2.7 0.4 5.0 1.0 22.4

11

Scheme 1.3. A Diels-Alder cycloaddition catalyzed by various thioureas.

Another advantage for installing meta- and para-electron withdrawing substituents was

that the ortho-hydrogen atoms become more polarized and form an intramolecular

interaction with the sulfur atom lone pairs, thereby restricting rotation of the aromatic

substituents in the activated complex with the substrate (Figure 1.9). Schreiner reported

that the barrier of rotation for thiourea 1.18 is estimated to be more than twice than that

for thiourea 1.16 (3.4 kcal/mol and 1.5 kcal/mol, respectively).64 These results suggest the

catalyst-substrate complex is more favorable in rigid systems since the entropy loss of

flexible catalysts cannot be overcome by enthalpic effects. The most reactive of these

thioureas was subsequently named Schreiner’s thiourea (1.18) and is still recognized as

a gold standard in thiourea organocatalysis.

Figure 1.9. Intramolecular interaction between the ortho-hydrogens and sulfur atom in

thiourea 1.18 as it activates α,β-unsaturated ketone 1.14.

12

Due to the simple construction of the thiourea functional group (Scheme 1.1), chiral

thiourea catalysts have received significant attention for asymmetric catalysis.40,52,65

Design strategies have included one or more stereogenic groups (Figure 1.10) to induce

chiral active sites and the library of compounds that have been investigated is quite large.

Figure 1.10. Thioureas bearing one or two chiral scaffolds.

In addition, the inclusion of another functional group that acts as a Brønsted base,

Lewis base, or Lewis acid has shown to have a significant impact on the reactivities and

selectivities of Brønsted acid organocatalysts.65 This synergistic effect is known as

bifunctionality and results from multiple coordination sites within the catalyst’s structure.

For (thio)ureas, the Brønsted acidic N-H bonds activate the electrophile and a Lewis basic

functional group interacts with the nucleophile to promote chemical transformations

(Figure 1.11). In this dissertation, frameworks developed by Jacobsen, Takemoto, and

Ricci will be highlighted.

Figure 1.11. Generic activation mode by a chiral, bifunctional thiourea.

13

Thioureas that contain Schiff-base scaffolds are known as Jacobsen’s thioureas. A

large family of derivatives were first designed based on theoretical calculations to

maximize catalytic activation of aldimines and ketoimines.66 Over the last few decades, a

wide array of these compounds have been synthesized and have shown to be effective

catalysts in asymmetric processes such as Strecker (Scheme 1.4),66,67 Henry,68

Mannich,69 hydrophosphonylation,70 and acyl Pictet-Spengler reactions.71

Scheme 1.4. Asymmetric Strecker reaction catalyzed by a Jacobsen thiourea.

Takemoto et al. developed and investigated thioureas bearing a 3,5-

bis(trifluoromethyl)phenyl substituent and a chiral diaminoethane moiety (Figure 1.12).53,72

Cyclic (1.19 and 1.20) and acyclic (1.21) anti-diamines have been shown to be the most

effective structural motifs. A pendant tertiary amine was proposed to maximize catalytic

activity, since steric hinderance prevents the basic and acidic sites from binding one

another. However, thioureas with a primary amine have been investigated.73

14

Figure 1.12. Variations of Takemoto’s catalysts.

These bifunctional catalysts facilitate a variety of chemical transformations via

interactions with the electrophile and nucleophile.53,65,72 The first report was published in

2003, where thiourea 1.19 was found to be an efficient catalyst in a Michael addition of

malonates to nitroolefins (Scheme 1.5).74

Scheme 1.5. Enantioselective Michael reaction catalyzed by thiourea 1.19.

In a subsequent study, Takemoto et al. explored the catalyst’s structure, lowered the

catalyst loading to 2 mol%, and expanded the reaction scope to include generation of

chiral quaternary carbon centers.75 Kinetic studies were used to propose a reaction

mechanism catalyzed by these bifunctional thioureas and the proposed interaction of the

bifunctional catalyst and the substrates is shown in Figure 1.13. Following Takemoto’s

initial reports, the same laboratory has employed this bifunctional amino-thiourea strategy

for a variety of asymmetric transformations such as other Michael additions,76 aza-

Henry,77,78 Mannich,79 and hydrazination80 reactions.

15

Figure 1.13. Interactions between thiourea 1.19 and two substrates undergoing a Michael

addition.

Another commonly exploited chiral motif in asymmetric thiourea catalysis is the cis-1-

amino-2-indanol scaffold (highlighted in catalyst 1.22 in Scheme 1.6).81,82 This

commercially available framework provides structural rigidity in the catalyst and the

pendant hydroxyl group can act as a hydrogen bond donor or acceptor, affording different

binding modes with a variety of substrates. The first report using this strategy came from

Ricci et al. where thiourea 1.22 catalyzed an asymmetric Friedel-Crafts alkylation between

indole (1.23) and trans-β-nitrostyrene (1.24).83

Scheme 1.6. A Friedel-Crafts alkylation between 1.23 and 1.24 catalyzed by thiourea

1.22.

16

In a series of control experiments, the authors deduced that the pendant alcohol group

is crucial for enhanced reactivity and selectivity. In their proposed transition state (Figure

1.14a), the nitroalkene 1.24 is activated through the binding of its oxygen atoms with the

N-H bonds of the thiourea moiety, whereas the nucleophile (1.23) donates a hydrogen

bond to the hydroxyl group of the catalyst. In a follow-up report,84 Herrera et al. provided

computational evidence in support of these proposed interactions, but also found the

hydroxyl moiety interacts with the nitroolefin as a hydrogen bond donor (Figure 1.14b).

Thioureas/ureas bearing this aminoalcohol substituent have been shown to be efficient

catalysts for 1,4-additions into nitroalkenes,85–88 α,β-unsaturated acyl phosphonates,89

β,γ-unsaturated α-ketoesters,89,90 and enoates91 with a variety of nucleophiles, and have

promoted Henry87 and aza-Henry92 reactions.

Figure 1.14. Transition states proposed for the Friedel-Crafts alkylation between 1.23 and

1.24 facilitated by thiourea 1.22.

Despite all of the successful research on ureas and thioureas, a common drawback is

self-association through the oxygen or sulfur atoms with the N-H bonds (Figure 1.15),

leading to less, “free” active catalyst in solution. While this interaction is more favorable

for ureas,60,61 thioureas can still inhibit their own reactivities through dimerization.

17

Figure 1.15. Self-aggregation of ureas and thioureas.

To address this, there have been some strategies to minimize this effect and afford

more reactive catalysts. Internal methods generally include exploiting one or more

intramolecular hydrogen bonds to bind the oxygen or sulfur atom of the (thio)urea (Figure

1.16). This interaction was first recognized in Schreiner’s thiourea 1.18, where the ortho-

hydrogens in the aromatic ring were found to coordinate with the sulfur atom (see Figure

1.9). Inspired by this, Seidel et al. replaced the phenyl ring with a protonated pyridine to

increase this intramolecular interaction (1.25).85 Lewis acids such as boron93–96 and

palladium97 have also been exploited to chelate the sulfur/oxygen atom (1.26). Lastly,

using a larger network of hydrogen bonds has been investigated (1.27).98,99

Figure 1.16. Internal strategies to prevent urea/thiourea self-aggregation and improve

catalytic reactivity.

18

In contrast, the addition of a Brønsted or Lewis acid cocatalyst to break up self-

aggregation has also been shown to have a significant impact on the reactivities and

selectivities of these hydrogen bonding catalysts (Figure 1.17). Reports from the Herrera

laboratory have shown that the addition of an external Brønsted acid affords a more

reactive and selective urea analogue of 1.22 toward the Friedel-Crafts alkylation of indoles

(1.23, Scheme 1.6) and trans-β-nitrostyrenes (1.24).100,101 In general, yields improved by

20-60% and selectivities (ees) were doubled when the additive was employed for a variety

of substituted substrates. In a similar manner, complexes of various metals (M = Ag, Au,

and Cu) with thiourea 1.22 and similar analogues were investigated and the same general

trend was observed.102

Figure 1.17. External strategies to prevent urea/thiourea self-aggregation and improve

catalytic reactivity.

1.4.2 BINOL

Another class of asymmetric organocatalysts are chiral diols. The most common of

which are 1,1’-bi-2-naphthol (BINOL, 1.28) and α,α,α’,α’-tetraaryl-1,3-dioxolan-4,5-

dimethanol (TADDOL, 1.29). These compounds have been widely used as chiral ligands

for metal-centered asymmetric catalysis.44,103–106 In recent years, these molecules have

been shown to independently catalyze reactions through hydrogen bonds.42,43,107 While

they have the potential to donate two hydrogen bonds similar to (thiou)ureas, TADDOLs

have been shown to form an intramolecular hydrogen bond which promotes the other

19

hydroxyl hydrogen for substrate activation (Figure 1.18).108 The corresponding hydrogen

bond scenarios with BINOLs are unclear in most cases.

Figure 1.18. Popular chiral diols for hydrogen bonding catalysis.

The popularity of the binaphthyl backbone (1.28) in organocatalysis stems from its

rigid, axis of chirality. This scaffold is resistant to racemization due to the steric hinderance

of the 8,8’- hydrogens and 2,2’ substituents (Figure 1.19).109 However, this rotation barrier

can be overcome under certain conditions with Pd110 or acid/base.111

Figure 1.19. Rotational hinderance positions in BINOL.

Research on BINOL derived compounds has highlighted synthetic methodologies for

introducing substituents on the ring skeleton at a variety of positions. Bromination of 1.28

affords synthetic handles at the 6,6’-positions (1.30, Scheme 1.7).112 Hydrogenation

affords H8-BINOL (1.31),113 which provides a more rigid catalyst than the fully aromatic

framework (Scheme 1.8).114 Lastly, derivatization of the 3,3’-positons has been achieved

20

in 3-4 steps,115 and these substituents have been shown to significantly impact the

reactivities and selectivities of the ligands or catalysts bearing this scaffold (1.32, Scheme

1.9).115

Scheme 1.7. Bromination of the 6,6’-poisitions of BINOL.

Scheme 1.8. Synthesis of H8-BINOL by hydrogenation of BINOL.

Scheme 1.9. Generic route to 3,3’-substituted BINOLs.

Despite these advantages and pathways for derivatization, BINOLs have been largely

ignored as independent hydrogen bond donors. This is due to their relatively weak

acidities,116 and much stronger acids such as phosphoric acids can be made from them in

21

one step (1.33, Scheme 1.10).117 Thus, BINOL-based phosphoric acids and

phosphoramides have dominated the field of organocatalysis in recent years.107,118

Scheme 1.10. Synthesis of BINOL-based phosphoric acids.

The first reported transformation catalyzed by BINOL as an independent hydrogen

bond donor was a Baylis-Hillman reaction between cyclopent-2-en-1-one (1.34, Scheme

1.11) and 3-phenyl-1-propanal (1.35) in the presence of tributylphosphine (1.36).119 In this

study, racemic catalysts were used, so the stereoselectivity was not investigated.

Scheme 1.11. A Bayliss-Hillman reaction catalyzed by BINOL.

22

BINOL 1.28 afforded quantitative yield of the desired product in 1 h. Conversion of one

hydroxyl group to a methyl ether (1.37) led to an 80% yield under the same conditions.

These results indicate that the presence of two hydrogen bond donors affords a higher

yield, but this experiment does not reveal whether 1.28 acts as a single or double hydrogen

bond donor. Elimination of both hydrogen bond donors (1.38) led to no catalytic reactivity

as the same result was observed when no catalyst was added (23-24% yield). After

screening these Brønsted acid catalysts, a substrate scope including different α,β-

unsaturated ketones and esters and other aliphatic aldehydes was investigated.119

Inspired by this work, McDougal and Schaus employed enantiopure BINOL and H8-

BINOL catalysts and studied their reactivities and enantioselectivities in a Morita-Baylis-

Hillman reaction between 3-phenyl-1-propanal (1.35, Table 1.2) and cyclohex-2-en-1-one

(1.39) in the presence of triethylphosphine (1.40).120 Without any Brønsted acid catalyst

(entry 1), the reaction was very slow, affording a 5% yield after 36 h. Use of (R)-BINOL

1.28 and (R)-H8-BINOL 1.31 (entries 2 and 3) led to significantly higher yields (73-74%)

and selectivities of 32 and 48% ee, respectively. Due to these results, a series of 3,3’-

substituted H8-BINOLs were investigated and large, electron-withdrawing substituents

such as Br (1.41) and 3,5-bis(trifluoromethyl)phenyl (1.42) provided interesting results. In

entry 4, catalyst 1.41 showed similar reactivity (73% yield) to the parent compounds (1.28

and 1.31), but the enantiopurity of the product rose to 79% ee. The best reactivity (84%

yield) and selectivity (86% ee) was obtained with catalyst 1.42 (entry 5). These results

indicate a more acidic and sterically encumbered catalyst is important for obtaining

efficient reactivity and good stereoselectivity.

23

Table 1.2. Asymmetric Morita-Baylis-Hillman Reactions Catalyzed by BINOL and H8-

BINOL Hydrogen Bonding Catalysts.a

After screening the structures of the BINOL catalysts, a substrate scope of the

aldehydes was examined. In general, aliphatic aldehydes reacted well with >70% isolated

yields and selectivities of >90% ee. Conjugated aldehydes were also employed but lower

yields and enantioselectivities were observed.120

A similar catalyst scope of BINOL and H8-BINOL derivatives were employed as

hydrogen bond catalysts in an enamine Mannich reaction (Table 1.3).121 The background

rate of the reaction under these conditions was negligible as no product was isolated after

entry catalyst Yield (%)b ee (%)c

1 none 5 -

2 (R)-1.28 74 32

3 (R)-1.31 73 48

4 (R)-1.41 73 79

5 (R)-1.42 84 86

aReactions were run under argon with 1 mmol of 1.40 and 1.35, followed by chromatography on silica

gel. bIsolated yield. cDetermined by chiral HPLC.

24

3 days (entry 1). Comparing entries 2 and 3, (R)-BINOL 1.28 afforded a 65% yield of

racemic product, whereas (S)-H8-BINOL 1.31 was found to lead to more conversion (89%

yield) and selectivity (63% ee). Thus, (S)-H8-BINOL derivatives were explored. A poorer

yield and ee were observed with the 3,3’-dibromo variant 1.41 while the di-3,5-

bis(trifluoromethyl)phenyl derivative 1.42 led to the smallest conversion but the same

selectivity as obtained by H8-BINOL. Thus, the parent compound 1.31 was the most active

and selective catalyst examined in this work, contradictory to most reports regarding 3,3’-

substituted BINOL-based organocatalysts.115

Table 1.3. An Enamine Mannich Reaction Catalyzed by BINOL and Catalyzed by

BINOL and H8-BINOL Hydrogen Bonding Catalysts.

entry catalyst Yield (%)a ee (%)b

1 none - -

2 (R)-1.28 65 0

3 (S)-1.31 89 63

4 (S)-1.41 50 20

5 (S)-1.42 33 65

aIsolated yield. bDetermined by chiral HPLC.

25

A third report found that a reaction between dienamine 1.43 and nitrosobenzene (1.44)

could be catalyzed by 3,3-substituted BINOL hydrogen bond donors (Table 1.4).122 The

bicyclic product appears to be the result of a hetero-Diels-Alder cycloaddition followed by

hydrolysis of the resulting enamine (Scheme 1.12). However, control experiments and

computational studies revealed that the reaction likely proceeds via a N-nitroso aldol

reaction followed by a Michael addition. Subsequent hydrolysis of the morpholine group

would then afford the observed product.122

Scheme 1.12. Proposed mechanistic pathways for the illustrated transformation.

In entry 1, use of unsubstituted (S)-BINOL 1.28 led to good reactivity but poor

selectivity under the employed reaction conditions (78% yield, 28% ee). Inspired by this

result, the authors synthesized a variety of BINOL derivatives with bulky substituents at

the 3 and 3’-positions such as triisopropylphenyl (commonly abbreviated as TRIP, 1.45)

and triaryl silyl groups (1.46). Use of these bulkier catalysts led to decreased yields

compared to the parent compound 1.28, but improved selectivities were observed. That

is, the TRIP-substituted BINOL 1.45 (entry 2) afforded a 31% yield of the desired product

with 46% ee (about twice as selective as catalyst 1.28). The silylated derivative 1.46

26

afforded better reactivity than 1.45 (57% yield) and was the most selective catalyst that

was studied (90% ee).

Table 1.4. N-Nitroso Aldol/Michael Addition Catalyzed by BINOL Derivatives.

Given the results in Tables 1.2 – 1.4, a delicate balance between the electronic and

steric interactions of the active site of the BINOL catalyst need to be considered. A better

understanding of this relationship would provide guidance for BINOL and H8-BINOL

hydrogen bonding catalysts.123 Furthermore, the number of reactions that have been

examined using these chiral diols as hydrogen bonding catalysts is very low compared to

(thio)ureas or phosphoric acids. Other transformations that have been tried in which

substituted BINOLs were used as purely hydrogen bond donating catalysts include a


1 (S)-1.28 78 28

2 (S)-1.45 31 46

3 (S)-1.46 57 90


27

Diels-Alder cycloaddition,124 a Friedel-Crafts alkylation,124 and an addition to imines.125 In

these reports, the reactivities and/or the selectivities were poor (i.e., slow reaction rates

and/or racemic products were formed).

1.5 Design Strategies for Enhanced Brønsted Acid Organocatalysts

Current research in hydrogen bond catalysis aims to increase the reactivities and

selectivities of these catalysts126 and broaden the scope of reactions and substrates that

can be activated. One method for improving their efficiency is introducing another

hydrogen bond donor or acceptor such as Jacobsen’s and Takemoto’s thioureas (see

Section 1.3.1). These new interactions can change the active site of the compound or

improve the catalyst-substrate interaction, leading to more efficient transformations.127

Another popular strategy focuses on lowering the pKa of the catalysts, thereby

facilitating reactions through stronger interactions. Since Schreiner’s work with thioureas

(Scheme 1.3),64 correlations between the acidity of the hydrogen bond catalyst and its

reactivity and enantioselectivity has been reported numerous.51,128,129 Thus, electron-

withdrawing groups are commonly embedded into catalyst structures to increase their

acidities.126 The most widely used substituent for this purpose is the bis(3,5-

trifluoromethyl)phenyl moiety, which has become a privileged scaffold for a variety of

Brønsted acid organocatalysts.130,131

The correlation of acidity and reactivity of Brønsted acid catalysts has been

investigated by Sigman and Jensen.132,133 A series of acetamide catalysts (1.47) with a

range of over 3 pKa units62 were synthesized and their reactivities and enantioselectivities

were observed in a Diels-Alder cycloaddition (Table 1.5).

28

Table 1.5. Comparison of Acidity and Reactivity in a Diels-Alder Cycloaddition.

As shown in Table 1.5, the most acidic derivative was found to be the most reactive

and selective catalyst. When a more acidic catalyst is employed, the binding affinity

towards the substrate is increased.132 That is, the catalyst-substrate complex is more

favorable to form, causing an increase in the reaction rate. Sigman and Jensen also

speculated that a more acidic catalyst forms a stronger hydrogen bond with the substrate,

increasing the activation of the substrate and imposing higher enantioselectivity due to a

more rigid activated complex.132 Thus, acid-base trends of organic molecules have

significant influence on the efficiency of these hydrogen bond donors.

1.6 Acidity in Nonpolar Solvents

Brønsted acids are most commonly characterized by their pKa values which are

generally determined in polar solvents such as water,134 dimethyl sulfoxide (DMSO),62 and

entry R pKa (DMSO) Yield (%)a ee (%)b

1 CF3 -0.25 67 91

2 CCl3 0.65 61 81

3 CHCl2 1.29 53 75 4 CH2F 2.66 17 62 5 CH2Cl 2.86 32 52


29

acetonitrile.135 Substituent effects are also typically studied in high dielectric media,136,137

where the solvent separates the newly formed ion pairs. However, hydrogen bonding

organocatalysts are routinely employed in less polar media such as chloroform, toluene,

and dichloromethane where aggregation of oppositely charged ions is more favorable.

Thus, catalytic reactivities predicted by pKa values may be misleading. To address this

issue, multiple analytical techniques have been developed to better assess hydrogen bond

donating abilities in nonpolar solvents.

1.6.1 UV-Vis Spectroscopic Titration

The first method for rapid quantification of activating effects of hydrogen bonding

catalysts with UV-vis spectroscopy was developed from the laboratory of Dr. Marisa

Kozlowski (Scheme 1.13).124,138 A red, colorimetric sensor molecule (7-methyl-2-

phenylimidazo[1,2-a]pyrazine-3(7H)-one, 1.48) was titrated with a hydrogen bond donor

in dichloromethane, where a blue-shift in the absorption maxima (λmax) was observed due

to the resulting hydrogen bonded complex 1.49. A binding constant (K), or the acid’s

affinity to bind the sensor molecule, was also obtained from this titration.

Scheme 1.13. UV-vis sensor 1.48 and its bound complex with a Brønsted acid (HX).

In the complete report,124 33 hydrogen bond donor catalysts with different structural

motifs were examined using this method. The reciprocals of the differences in the λmax

30

values between 1.48 and 1.49 were found to correlate with the logarithms of the binding

constant (K) and the rate constant (k) for a Diels-Alder cycloaddition. The pKa values of

the Brønsted acids, however, did not correlate with the reactivities of all of the compounds

in the study, but only within specific catalyst classes (i.e., ureas versus phenols). The

library of compounds examined with this technique has recently been expanded as has

the experimental approach for carrying out this assay.139,140

1.6.2 A 31P NMR Titration Method

A similar methodology for quantifying the hydrogen bonding strength of Brønsted acids

has been reported using 31P NMR spectroscopy.141,142 Trialkylphosphine oxides (1.50)

were used as 31P NMR probes, where upon addition of a hydrogen bond donor, a

downfield shift in the 31P NMR signal was observed as a result of complexation between

the probe and Brønsted acid (Scheme 1.14).

Scheme 1.14. Quantification of hydrogen-donating ability by observing the change in the

31P NMR chemical shift of phosphine oxides (1.50) and their bound complexes with

Brønsted acids (HX).

In the first report,141 only thioureas were examined and the change in the 31P NMR

chemical shift (Δδ(31P)) between the free and bound phosphine oxides correlated with the

logarithm of the rate constants (k) for a Diels-Alder cycloaddition better than the pKa values

of the thiourea catalysts. In a later study,142 the scope was expanded to include phenols,

31

carboxylic acids, squaramides, silanols, phosphoric acids, and boronic acids, and their

activities were compared in a Friedel-Crafts alkylation. Once again, the observed Δδ(31P)

values correlated with reaction rates better than pKa values collected in water or DMSO.

1.6.3 IR Spectroscopy

A third method to determine hydrogen bond donating ability in nonpolar media was

examined with IR spectroscopy by Samet et al. in the Kass group (Figure 1.20).143 In this

report, substituted phenols were dissolved in carbon tetrachloride and their O-H stretching

frequencies were collected, both in the absence (blue) and presence (red) of a hydrogen

bond acceptor (i.e., CD3CN). Larger differences in these stretching frequencies (Δʋ) are

in accord with stronger hydrogen bonds and better hydrogen bond donors.144 The authors

found that Δʋ correlates with the gas-phase acidities (ΔG°acid) of the phenols better than

their pKa values determined in DMSO, suggesting that the former quantities provide a

better guide to the acidities of phenols for nonpolar media.

Figure 1.20. IR spectra of phenol in CCl4 in the absence (blue) and presence (red) of d3-

acetonitrile.

32503350345035503650

Wavenumber (cm-1)

32

Charged groups have the largest effect on acidity in the gas phase.145,146

Deprotonation of a positively-charged molecule leads to an overall neutral species (either

as a zwitterion or removal of both charged centers through resonance or a chemical

transformation) which is an extremely stabilizing force in the absence of a solvent. Thus,

positively charged Brønsted acids were hypothesized to have enhanced acidities and

catalytic efficiencies in nonpolar media. To test this idea, N-octylammonium (1.51) and N-

octyl-3-hydroxypyridinium (1.52) ions with a weakly coordinating anion, tetrakis (3,5-

bis(trifluoromethyl)phenyl)borate (1.53, BArF4-), were synthesized and compared to 4-

nitrophenol (1.54), the most acidic neutral analogue in the study. The DMSO pKa values,

gas-phase acidities (ΔG°acid), and frequency shifts for their O-H stretches (Δʋ) are given

in Table 1.6.143

Table 1.6. Comparison of pKa values, gas-phase acidities, and hydroxyl frequency

shifts (Δʋ) of Charged and Neutral Phenols.

entry cmpd pKa (DMSO) ΔG°acid (kcal mol-1) Δʋ (cm-1)

1 1.54 10.8 320.9 221

2 1.51 12.4 261.4a 329

3 1.52 12.5 231.1a 370

aComputed B3LYP/6-31+G(d,p) values at 298 K.

33

The most acidic neutral analogue in the study (1.54) was found to be about 2 pKa units

more acidic in DMSO compared to the charged species (pKa = 10.8 versus 12.5,

respectively). However, 1.54 has a gas-phase acidity of 320.9 kcal mol-1, whereas the

ammonium (1.51) and pyridinium (1.52) ions have much smaller ΔG°acid values (261.4 and

231.1 kcal mol-1, respectively). These results indicate the charged compounds are more

acidic than 4-nitrophenol (1.54) by about 44 (1.51) and 66 (1.52) pKa units in the gas-

phase at 298 K. The same trend was observed with the IR method where the O-H

frequency shifts are 221 cm-1 for 1.54, 329 cm-1 for 1.51, and 370 cm-1 for 1.52. To address

these contradictory predictions (i.e., the relative gas phase acidities vs DMSO pKa’s),

these compounds were employed as catalysts in a Friedel-Crafts alkylation between N-

methylindole (1.55) and trans-β-nitrostyrene (1.24, Scheme 1.15).143 This reaction is well-

studied and it has been shown that in general the stronger the acid catalyst, the faster the

observed reaction rate.85,127 Thus, this transformation is a good test reaction for comparing

the reactivities of many Brønsted acid and hydrogen bonding catalysts.

Scheme 1.15. Reactivities of neutral and charged phenol derivatives in a Friedel-Crafts

alkylation.

34

It was found from the kinetic study noted above that the neutral phenol 1.54 was an

inefficient catalyst as the observed half-life is 4100 h (i.e., about 171 d or nearly 6 months).

In contrast, the ammonium and pyridinium ions 1.51 and 1.52 were significantly more

active catalysts, leading to half-lives of 64 h (about 2.5 d) and 2.1 h, respectively. This

reactivity order is in accord with the ΔG°acid values and the changes in the O-H stretching

frequencies (Δʋ), indicating that the gas-phase acidity values are a better guide than the

DMSO pKa’s for relative catalytic abilities in nonpolar media. This study has been the

foundation for subsequent research in the Kass group over the last 5 years.

1.7 Charge-Enhanced Brønsted Acid Catalysts

1.7.1 Charged-Enhanced Thioureas

Since the discovery that charged substituents have a significant impact on acidity in

nonpolar solvents, research in the Kass group has focused on implementing this strategy

into well-studied hydrogen bond donors. The first report came from Yang Fan,147 who

synthesized singly (1.56) and doubly (1.57) charged thioureas and employed them as

catalysts in a variety of chemical transformations (such as Scheme 1.16).

In the Friedel-Crafts alkylation between N-methylindole (1.55) and trans-β-nitrostyrene

(1.24, Scheme 1.16), the charged compounds were found to outperform the most active

thiourea at the time, Schreiner’s thiourea (1.18). That is, the reactions catalyzed by the

mono- (1.56) and di-charged (1.57) variants were about 7 and over 400 times more

reactive than 1.18, respectively. The same reactivity trend was observed from results

obtained with a Diels-Alder cycloaddition and a solvent free aminolysis of an epoxide.147

35

Thus, a single charged center was found to afford more reactivity than four trifluoromethyl

groups.148

Scheme 1.16. A Friedel-Crafts alkylation catalyzed by neutral and charged thioureas.

Yang Fan continued to examine these charge-enhanced thioureas139,149 by

investigating chiral variants and observed their reactivities and enantioselectivities.150

Various mono-charged thioureas bearing the cis-1-amino-2-indanol moiety (1.58) were

synthesized and employed as catalysts in the Friedel-Crafts alkylation of indoles and

nitrostyrenes (Scheme 1.17). Excellent yields could be achieved at room temperature, and

the best selectivities (up to 95:5 er) were observed when the reaction was conducted at -

35 °C.150

Scheme 1.17. An asymmetric Friedel-Crafts reaction catalyzed by thiourea 1.58.

36

1.7.2 Charged-Enhanced Phosphoric Acids

Jie Ma of the Kass group employed this charge-enhanced strategy in achiral

phosphoric acids and compared their reactivities to the widely used diphenyl substituted

phosphoric acid 1.59 (diphenyl phosphate or DPP).151 In this study, singly (1.60) and

doubly (1.61) charged phosphoric acids were found to be more reactive and

diastereoselective than DPP in Diels-Alder cycloaddition (Table 1.7).

Table 1.7. A Diels-Alder Cycloaddition Catalyzed by Various Achiral Phosphoric

Acids.

Under the same conditions DPP (1.59) afforded an 81:19 endo/exo product ratio with

a reaction half-life of 61 h (over 2.5 d), whereas the mono (1.60) and doubly (1.61) charged

variants gave 88:12 endo/exo ratios with half-lives of 3.7 min and 1.5 min, respectively.

The same reactivity order was observed in a Friedel-Crafts alkylation and a ring-opening

polymerization.151

entry catalyst t1/2 (h) krel endo/exo

1 1.59 61 1.0 81:19

2 1.60 3.7 min 1000 88:12

3 1.61 1.5 min 2500 88:12

37

Following this preliminary investigation of achiral phosphoric acids, Jie Ma examined

chiral variants by synthesizing a variety of doubly-charged, BINOL-based phosphoric

acids.152,153 With this catalyst framework, the binaphthyl backbone affords an axis of

chirality and substituents at the 3 and 3’ positions have been shown to be crucial for

obtaining more selective transformations.35 Taking these details into account, Ma

embedded the positively charged centers through phosphonium ions at the 3 and 3’-

positions (1.62), and compared these catalysts to neutral analogues 1.63 and 1.64 (Figure

1.21).

Figure 1.21. BINOL-based phosphoric acids bearing phosphonium ion, triphenylsilyl, and

TRIP substituents in the 3- and 3’-positions.

In the first report from Ma and Kass, the phosphonium phosphoric acids were

compared to commonly used, neutral phosphoric acids in a Friedel-Crafts reaction

between indole (1.23) and 2,2,2-trifluoroacetophenone (1.65, Table 1.8).152 The dicationic

phosphoric acid 1.62 exhibited excellent reactivity (93% yield) and enantioselectivity (96%

ee) for this transformation. The neutral analogues (1.63 and 1.64) also afforded excellent

enantioselectivities of 93 and 97% ee, respectively, but their catalytic reactivities were

inferior compared to Ma’s charged species. That is, less than 10 and 50% of the desired

product was obtained in reactions using catalysts 1.63 and 1.64, respectively, whereas

38

the reaction was nearly complete in the same amount of time when phosphoric acid 1.62

was employed. Thus, the phosphonium ion strategy was shown to afford higher reactivity

compared to neutral analogues while maintaining high levels of enantioinduction for this

reaction.

Table 1.8. Asymmetric Friedel-Crafts Reaction Catalyzed by BINOL-based

Phosphoric Acids.

After screening the BINOL-based catalysts, the substrate scope was examined with

catalyst 1.62. With a few exceptions, high yields (82-96%) and enantioselectivities (84-

96% ee) could be obtained for reactions involving substituted indoles and other 2,2,2-

trifluoroacetophenone derivatives.152

These phosphonium-ion-tagged phosphoric acids were also investigated in an

asymmetric Friedel-Crafts reaction with indole (1.23) and trans-β-nitrostyrene (1.24),

where >99% conversions and up to 90% ee could be obtained (Scheme 1.18).153 In this

report, a similar trend was observed, where the charged catalysts (1.62) were more

reactive and selective than their neutral analogues (1.63 and 1.64).


1 1.62 93 96

2 1.63 9 93

3 1.64 43 97 aIsolated yield. bDetermined by chiral HPLC.

39

Scheme 1.18. An asymmetric Friedel-Crafts reaction catalyzed by BINOL-based

phosphoric acids.

1.8 Thesis Focus

This dissertation focuses on improving the reactivities and enantioselectivities of

charge-enhanced Brønsted acids. The syntheses and characterization of many hydrogen

bond donors will be discussed, as well as a variety of analytical methods used to observe

their reactivities and selectivities. In Chapter 2, computations and IR and UV-vis

spectroscopic measurements were employed to predict catalytic activities of O-H, N-H,

and C-H charge-enhanced acids. An analytical investigation of the reliability of enantiomer

excess measurements obtained by chiral HPLC is presented in Chapter 3. In Chapter 4,

evaluation of a charged thiourea catalyst revealed a strategy for improved reactivity and

selectivity, and its reaction scope was expanded. A computationally designed thiourea

was proposed, synthesized, and studied in Chapter 5. Lastly, Chapter 6 details the

syntheses of new electrostatically-enhanced BINOL catalysts.

40

Chapter 2: Structural Considerations for Charge-Enhanced Brønsted Acid

Catalysts*

2.1 Introduction

Enzymes exploit hydrogen bonds to control their three-dimensional structures,

facilitate substrate molecular recognition and binding, and accelerate reaction processes.1

Their catalytic ability is intertwined with numerous chemical mechanisms, but often

involves electrophilic activation of a substrate toward nucleophilic attack by lowering the

energy of its lowest unoccupied molecular orbital (LUMO).2 As a result, the development

of small metal-free Brønsted acids and hydrogen bond donors to catalyze a wealth of

organic transformations has emerged as an attractive research area in the past several

decades.3 From these studies it has been found that for the same class of compounds

with the same binding motifs, that the acidity of the catalyst often correlates with its

activity.4 It is for this reason that electron-withdrawing substituents are commonly

employed to improve reactivity.5 For example, phenyl rings are routinely replaced by

bis(3,5-trifluoromethyl)phenyl groups, and this latter framework is viewed as occupying a

privileged position.6

Brønsted acids are routinely characterized by their pKa values which typically are

measured in water, dimethyl sulfoxide, or acetonitrile.7 These solvents have high dielectric

constants which facilitate the acidity determinations and lead to solvent separated ion

pairs. Brønsted acids and hydrogen bond donating organocatalysts, however, are usually

employed in nonpolar media such as toluene, chloroform, and dichloromethane where

* Reprinted (adapted) with permission from Payne, C.; Kass, S. R. Structural Considerations for

Charge-Enhanced Brønsted Acid Catalysts. J. Phys. Org. Chem. 2020. DOI: 10.1002/poc.4069. Copyright (2020) John Wiley & Sons, Ltd.

41

intimate ion pairs and aggregates are formed. Substituent effects and catalyst activities,

consequently may be poorly represented by routinely determined pKa values. To address

this issue, Kozlowski et al. developed a UV-vis spectroscopy approach in which a

colorimetric sensor, 7-methyl-2-phenylimidazo[1,2-a]pyrazine-3(7H)-one (2.1) is titrated

with a hydrogen bond donor (HX) in dichloromethane (Scheme 2.1).8 The reciprocals of

the observed blue-shifts of the bound complexes (2.1••HX) were found to correlate with

the logarithms of the association binding constants (K) and the rate constants (k) for the

Diels Alder reaction of cyclopentadiene with methyl vinyl ketone.

Scheme 2.1. UV-vis sensor 2.1 and its bound complex with a Brønsted acid.

More recently, we made use of IR spectroscopy to determine the relative acidities of

substituted phenols in carbon tetrachloride by examining the change in their O–H

stretching frequencies (Δʋ) upon addition of a small amount of a hydrogen bond acceptor

(i.e., CD3CN).9 It was found that Δʋ correlates with the gas-phase acidity more strongly

than DMSO pKa values. This led to the suggestion and observation that charged

substituents are much more effective at enhancing acidities and catalytic abilities than

neutral polar groups such as CF3, CN, and NO2. For example, it was found that the

Friedel-Crafts reaction between N-methylindole and trans-β-nitrostyrene in chloroform

occurs ~103 times more rapidly when N-octyl-3-hydroxypyridinium tetrakis[3,5-

42

bis(trifluoromethyl)phenyl]borate (BArF4) rather than when 4-nitrophenol is used as the

catalyst (eq. 2.1).

Since this discovery, achiral and chiral thioureas10 and phosphoric acids11 have been

investigated with this charge-activated design. In these reports, the charged center was

introduced most commonly with a 3-substituted N-alkylated pyridine ring.12 Other cationic

compounds such as amidinium,13 guanidinium,14 ammonium,15 pyridinium,16 and

quinolinium17 ions also have been shown to accelerate a variety of chemical

transformations.18 These protonated compounds are more acidic than their neutral

conjugate bases and have an additional hydrogen bond donating site that can alter the

binding motif of the catalyst, and enhance its association with the substrate. To address

the impact of the structural framework on catalyst activity, we report herein on all three

isomers of N-methylated and N-protonated hydroxypyridinium BArF4– salts along with the

two parent pyridinium ions (Figure 2.1). These compounds were probed by IR and UV-vis

spectroscopy, DFT and G4 theory computations,19 and a pseudo-first-order rate study.

43

Figure 2.1. Charged catalysts screened in this work.

2.2 Results and Discussion

N-Methyl-3-hydroxypyridinium BArF4 (2.3Me) was prepared by reacting 3-

hydroxypyridine with methyl iodide to afford N-methyl-3-hydroxypyridinium iodide, which

was then converted to the BArF4 salt by anion exchange with NaBArF

4 in dichloromethane

(Scheme 2.2).20 Alkylation of 2- and 4-hydroxypyridine in a similar manner afforded a

mixture of N- and O-alkylated products due to the tautomeric nature of the starting

substrates,21,22 and we were unable to obtain dry samples of the separated species.

Protonation of the corresponding N-methylpyridones, consequently was explored.

Aqueous acids (HI and HCl) led to the desired halide salts but problems were encountered

in trying to remove water from these compounds. To circumvent this issue, a one pot

protonation and anion exchange procedure was developed. Anhydrous HCl gas was

produced in situ23 and bubbled through a dichloromethane or 1,2-dichloroethane solution

containing the pyridone of interest and NaBArF4.

44

Scheme 2.2. Synthetic routes for all three isomeric N-methylhydroxypyridinium BArF4

salts.

This successfully led to 2.4Me but a minor byproduct that resisted purification arose in the

preparation of 2.2Me; we speculate that this impurity is an isomer of 2.2Me and

corresponds to N-protonation of N-methyl-2-pyridone. A satisfactory sample of the latter

compound was generated via its triflate salt, which is easier to handle and purify than the

corresponding halides, by reacting N-methyl-2-pyridone with neat triflic acid and taking

advantage of the differential solubility of NaOTf and NaBArF4 in dichloromethane. The one

pot procedure with gaseous HCl was also used to synthesize protonated pyridinium salts

2.2H, 2.3H, and 2.5H, but not 2.4H since 4-hydroxypyridine is insufficiently soluble in

CH2Cl2. In this latter case, 2.4H was prepared from its triflate salt in an analogous manner

to 2.2Me.

IR spectroscopy was used to assess the acidities and hydrogen bond donating abilities

of the N-methylated phenols in a nonpolar solvent. These salts are insufficiently soluble in

carbon tetrachloride, the solvent that was previously utilized,9 so dichloromethane-d2 was

45

used instead. The free and hydrogen bound O–H stretching frequencies for 2.2Me, 2.3Me,

2.4Me, phenol, and 4-nitrophenol were obtained in CD2Cl2 and a 1% (v/v) mixture of

CD3CN in CD2Cl2 (Table 2.1). Gas-phase acidities (ΔG°acid) of these compounds were

computed at 298 K using the highly accurate G4 composite approach and are also given

in Table 2.1. As shown in entries 1-5 in Table 2.1, a larger Δυ was observed for more

acidic compounds with smaller ΔG°acid values. For example, phenol has a gas-phase

acidity of 341.5 kcal mol–1 and afforded a difference in the O–H stretch of 170 cm–1 (entry

1), whereas ΔG°acid = 227.0 kcal mol–1 for 2.4Me and a frequency change of 398 cm–1

(entry 4) was found. The same trend was observed with the free O-H stretches with the

possible exception of 2.2Me, but the range was approximately four times smaller (i.e., 435

vs 102 cm–1 or ~4 vs 1 mol cm–1 kcal–1 given that the acidities span 114.5 kcal mol–1 from

341.5 to 227.0 kcal mol–1).25

Table 2.1. IR O-H and N-H Stretching Frequencies and Gas-Phase Acidities of a

Series of Phenol and Pyridinium Derivativesa

entry cmpd υ (cm-1)b

Δυ (cm-1)b,c ΔG°acid

(kcal mol–1)b,d CD2Cl2 1% CD3CN

1 C6H5OH 3582 3412 170 [157] 341.7 2 4-O2NC6H4OH 3559 3330 229 [221] 320.6 3 2.2Me <3501>e 2977 524 215.5 4 2.3Me 3513 3179 334 [370f] 234.3 5 2.4Me 3480 3082 398 227.0 6 2.5H (3307) (2903) (306) (214.9) 7 2.2Hg <3499>e (3316) 3071 (2962) 428 (354) 211.9 (211.0) 8 2.3Hg 3516 (3308) 3193 (2902) 323 (300) 230.1 (215.0) 9 2.4Hg 3477 (3348) 3249 (3107) 228 (241) 222.2 (218.7)

aSpectra collected using ~5 mM solutions of each compound in a 1 mm liquid cell. bParenthetical numbers are

for N–H stretches or acidities. cValues in brackets were obtained in CCl4 and taken from ref. 9. dComputed G4

theory values. Experimental acidities of 341.5 (PhOH), 320.9 (4-O2NC6H4OH), 213.9 (2.2Me), 214.9 (2.5H),

and 214.6 (2.3H) kcal mol–1 have been reported; see ref. 24. eThe O–H stretch was not observed and the

given value is a scaled (0.923) B3LYP/6-31G(2df,p) vibrational frequency. fThis value is for N-octyl-3-

hydroxypyridinium BArF4. gFree energies for the hydroxypyridines are computed to be lower in energy than

the corresponding pyridones (a zwitterion in the case of 2.3H) by 0.93 (2.2H), 3.46 (2.4H), and 15.1 (2.3H)

kcal mol–1.

46

Two acidic sites are present in the protonated series of hydroxypyridines, and as

expected, the O–H acidities for 2.2H-2.4H follow the same trend as 2.2Me-2.4Me (i.e.,

2.2Me (most acidic) > 2.4Me > 2.3Me (least acidic)). The N–H positions are calculated to

be the more acidic sites, but the differences are small for 2.2H and 2.4H (i.e., 0.9 and 3.5

kcal mol–1, respectively) due to tautomer formation upon O-deprotonation in these cases.

In contrast, a zwitterion results from 2.3H and the G4 acidity difference is much larger (i.e.,

15.1 kcal mol–1). A different acidity ordering of 2.2H > 2.3H > 2.4H is found, and is

surprising since one would expect the relative stabilities of these ions (i.e., 2.4H (0) > 2.2H

(0.5) > 2.3H (6.0 kcal mol–1)) to be inversely related to their acidities. 2-Hydroxypyridine is

9.5 kcal mol–1 more stable than 3-hydroxypyridine, however, due to a favorable O–H••N

electrostatic interaction. This energy difference is larger than that between 2.2H and 2.3H,

and is sufficient to reverse their acidities and account for why 2.2H is the more acidic

compound.

Both the N–H and O–H stretching frequencies for 2.2H-2.4H in the presence and

absence of CD3CN are given in Table 2.1. Computed values for all of the acids listed in

entries 1-9 along with their acetonitrile complexes are provided in the appendix, and the

former and latter values are linearly correlated with the observed stretching frequencies

(Figures S2 and S3, respectively). As expected, Δυ for both the N–H and O–H stretches

correlate with the gas-phase acidities of these positions although the linear correlation is

much tighter for the more acidic site (Figure 2.2). This is not surprising since one would

expect the initial acetonitrile to bind at the more acidic N–H position and only subsequently

coordinate at the O–H site.

47

Figure 2.2. Changes in the N–H (open circles) and O–H (filled circles) IR frequencies of

pyridinium BArF4– salts in CD2Cl2 upon addition of CD3CN versus the corresponding gas-

phase G4 acidities of the free ions. Linear least squares fits provide the following

equations: Δυ (cm–1) = -14.7 ΔG°acid + 3451, r2 = 0.991 (N–H acids) and Δυ (cm–1) =

-6.87 ΔG°acid + 1939, r2 = 0.662 (O–H acids with 2.4H omitted and not shown).

An alternative approach for assessing acids in non-polar solvents is to titrate them with

a colorimetric hydrogen bond accepting sensor (2.1), and monitor the resulting UV-vis

spectra to obtain changes in the absorption maxima along with 1:1 association binding

constants.8,10d An updated procedure was developed involving a non-linear fit of the

binding isotherm data, and well-defined isosbestic points were observed with 2.3Me,

2.4Me, 2.3H, and 2.5H. For example, over the course of adding 10 equivalents of 2.3H to

2.1 (Figure 2.3) an isosbestic point at 484 nm is observed and λmax of the bound complex

at 471 nm is readily obtained. These observations are consistent with a single intermediate

being formed between the Brønsted acid and UV/vis sensor (i.e., 1:1 binding). Different

behavior was found for 2.2Me, 2.2H, and 2.4H in that an apparent isosbestic point is seen

only when up to about 1 equivalent of the phenol is added (Figure 2.4 and Figures S14

and S16).26

200

250

300

350

400

450

500

550

200 210 220 230 240 250

Δυ

(cm

–1)

ΔG˚acid (kcal mol–1)

48

Figure 2.3. UV-vis spectra from 300 to 600 nm for the titration of 2.1 with 2.3H. For clarity

only half of the spectra are shown and they correspond to the addition of 0.00, 0.35, 0.69,

1.02, 1.67, 2.89, 5.59, and 10.7 equivalents of 2.3H.

It disappears upon further addition of the substrate due to a continuous blue shift that

occurs throughout the titration. This makes it difficult to obtain λmax for the 1:1 complex as

there is no clear endpoint in the titration. A new band also grows in at higher

concentrations of the hydrogen bond donor (e.g., the feature between 450-600 nm in

Figure 2.4), and this led to different colored solutions for 2.2Me and 2.2H.27 Taken

together, these observations indicate that more than one species is formed in these three

cases, and two or more equilibria are involved.

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

300 350 400 450 500 550 600

Absorb

ance

Wavelength (nm)

max(2.1••2.3H) max(2.1)

49

Figure 2.4. UV-vis spectra from 300 to 600 nm for the titration of 2.2Me with 2.1. For clarity

only half of the spectra are shown and they correspond to the addition of 0.00, 0.22, 0.44,

0.65, 0.76, 1.00, 1.50, 2.50, 5.80, 11.0, and 22.0 equivalents of 2.2Me.

To account for all of the above results, 1:1, 1:2, and 2:1 interactions with 2.1 were

considered for each of the pyridinium salts (Scheme 2.3). In the 1:2 complex, the two acids

presumably interact with the carbonyl oxygen and the β-nitrogen atom. B3LYP/cc-

pVTZ//B3LYP/cc-pVDZ and M06-2X/cc-pVTZ//M06-2X/cc-pVDZ computations on

2.1••PhOH are in accord with this view in that coordination at both of these sites are similar

in energy. That is, the enthalpy at 298 K for binding at the carbonyl oxygen as opposed to

the β-nitrogen is predicted to be favored by 2.11 and 1.37 kcal mol–1, respectively.

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

300 350 400 450 500 550 600

Absorb

ance

Wavelength (nm)

max(2.1••2.2Me)

max(2.1)

50

Scheme 2.3. Proposed binding modes for Brønsted acids such as 2.2Me with 2.1.

Alternatively, two molecules of 2.1 can interact with a single substrate (i.e., 2:1 binding)

if multiple hydrogen bonding sites are present in the catalyst, such as the N-H and O-H

bonds in 2.2H. For 2.2Me, we speculated that the hydroxyl group and carbon–hydrogen

bonds of the methyl substituent can serve as hydrogen bond donors.28 To assess this

possibility, N-methylpyridinium BArF4 (2.5Me) was prepared and examined. Its spectra

were well behaved and a clean isosbestic point was observed indicating a 1:1 association

with 2.1. This strongly suggests that the carbon-hydrogen bonds are sufficiently polarized

to lead to a binding interaction. Equilibrium association constants were determined using

the free online BindFit program and are given in Table 2.2.29,30 As expected, those

compounds that displayed clean isosbestic points throughout the titration are well fit by a

1:1 association model. The remaining three salts are best fit by 2:1 (2.2Me and 2.2H) and

1:2 (2.4H) binding schemes, although the latter scenario can be viewed as a 1:1

interaction of 2.1 with the dimer of 2.4H.

51

Table 2.2. Wavelength Shifts and Binding Constants from UV-vis Titrations with 2.1.

entry catalyst binding model λmax1:1 (nm)a,b K1:1 (M–1)b

1 2.2Mec 2:1 410.7 3.47 104

2 2.3Me 1:1 472.1 (471.7) 2.01 104

3 2.4Me 1:1 466.5 (465.6) 1.23 105

4 2.5Me 1:1 474.9 (474.9) 6.50 102

5 2.5H 1:1 470.3 (469.3) 1.78 105

6 2.2Hd 2:1 408.9 4.71 104

7 3.2H 1:1 470.6 (470.3) 6.05 104

8 4.2He 1:2 463.5 8.51 104

aWavelengths for the absorption maxima of the 1:1 complexes were obtained from a plot of χ / λmax at each

titration point, where χ is the 1:1 mole fraction resulting from the fit of the data; for additional details, see the

appendix. Parenthetical values correspond to observed λmax endpoints. bAverages of duplicate

measurements. cK2:1 = 1.44 x 104 M–1. dK2:1 = 8.42 x 103 M–1. eK1:2 = 1.23 x 104 M–1.

To explore this possibility, 1H NMR spectra of 2.4H were recorded and the OH, NH,

and aryl hydrogen chemical shifts were found to move downfield with increasing

concentration. A nonlinear fit of these results afforded a monomer-dimer equilibrium

constant (KD) of 1.3 x 103 M–1. Given this value, >99.99% of 2.4H exists as a monomer at

the mid-concentration used in the UV-vis titration with 1. In contrast, 2.3H and 2.3Me

(which afforded simple 1:1 behavior) were found to have smaller dimerization equilibrium

constants of 3.3 x 102 and 1.2 x 102 M–1, respectively.31 For both the methylated and

protonated series of pyridinium ions the binding equilibrium constants follow the same

order: 2.2 > 2.4 > 2.3 and ln K is found to linearly correlate with ΔG˚acid for the six

compounds that were fit by 1:1 or 1:2 binding models (Figure 2.5). The two ortho species

(2.2H and 2.2Me) are best described by 2:1 associations and their K1:1 values are smaller

than expected given their computed acidities.

52

Figure 2.5. Linear least squares fit of the logarithms of the 1:1 equilibrium association

constants between 2.1 and the pyridinium salts listed in Table 2.2 versus the G4 acidities

of the pyridinium ions. The equation for the line is ln K = -0.118 ΔG˚acid + 37.2, r2 = 0.882,

and the values for 2.2H and 2.2Me (open circles) were omitted from the regression.

Rate constants and reaction half-lives for the Friedel-Crafts alkylation of N-

methylindole with trans-β-nitrostyrene were obtained under pseudo-first order conditions

(Table 2.3).32 In the absence of a catalyst (entry 1), this transformation takes place

extremely slowly and has an estimated half-life of 3700 h or 155 days. Upon employing

10 mol% of 2.2Me–2.4Me (entries 2-4), rate constants spanning from 0.083 to 0.27 h–1

with half-lives between 2.5 and 8.3 h were observed. This leads to a reactivity order of

2.2Me > 2.4Me > 2.3Me, which is in accord with the IR data, the G4 acidities, and the UV-

vis λmax values for the 1:1 complexes noted above. The magnitudes of the 1:1 equilibrium

binding constants for 2.2Me and 2.4Me, however, are reversed. To verify that 2.2Me–

2.4Me are functioning as O–H hydrogen bond donating catalysts, 2.5Me was also

examined (entry 5) since the UV-vis data revealed that it associates with 2.1 even though

the hydroxyl group is absent. This species does catalyze the Friedel-Crafts reaction

4.0

5.0

6.0

7.0

8.0

9.0

10.0

11.0

12.0

13.0

14.0

200 210 220 230 240 250 260 270 280

ln K

(M–1)

DG˚acid (kcal mol–1)

53

relative to the background process even though all of the hydrogens are attached to

carbon atoms, but it is ~100–300 times less effective than 2.2Me–2.4Me. This is in accord

with the UV-vis results (i.e., λmax and K) and is consistent with the N-

methylhydroxypyridinium ions serving as O–H hydrogen bond donors.

Table 2.3. Kinetic Data for a Friedel-Crafts Reaction between N-Methylindole and

trans-β-Nitrostyrene.a

entry catalyst t1/2 (h)b k (h–1)b krel

1 - 3700 1.86 10-4 0.0022

2 2.2Me 2.5 2.73 10-1 3.3

3 2.3Me 8.3 8.33 10-2 1.0

4 2.4Me 4.2 1.67 10-1 2.0

5 2.5Mec 790 8.89 10-4 0.011

6 2.5H 2.7 2.58 10-1 3.2

7d 2.2H 0.47 1.49 18

8 2.3H 2.9 2.38 10-1 2.9

9 2.4H 3.7 1.83 10-1 2.2

10 2.6 5.9 1.17 10-1 1.4

a[N-methylindole] = 50 mM, [trans-β-nitrostyrene] = 500 mM. bAverage of duplicate trials. cBackground corrected data. dT = 25 °C.

For the protonated series of hydroxypyridinium BArF4– salts (entries 6-9), the reactivity

order is 2.2H > 2.5H, 2.3H > 2.4H and the half-lives range from under 30 minutes to 4

hours. Both 2.5H and 2.3H have similar catalytic activities, and this suggests that the latter

species also acts as a N-H hydrogen bond donor rather than an O–H Brønsted acid. The

same conclusion can be drawn for 2.2H and 2.4H since the protonated catalysts lead to

faster reactions than their corresponding N-methylated analogues (i.e., 2.2H > 2.2Me,

2.3H > 2.3Me and 2.4H > 2.4Me). Interestingly, 2.2H is significantly more active than all

54

of the other catalysts (entry 7), which implies that bidentate activation involving both the

N–H and O–H sites occurs in this case. To assess this possibility, 2-methoxypyridinium

BArF4 (2.6) was prepared from 2-methoxypyridine (Scheme 2.4)33 following the one pot

protonation and anion exchange method described above. This compound is

electronically similar to 2.2H and 2.4H, but is missing the O–H hydrogen bond donating

site. Its catalytic ability (entry 10) is comparable to 2.4H (half-lives of ~6 and 4 h,

respectively), but is more than an order of magnitude less than that for 2.2H. Given that

the dimerization equilibrium constant determined by 1H NMR for 2.6 is only 22 M-1 and a

factor of 10-100 times smaller than for 2.3H, 2.3Me, and 2.4H,34 it is likely that 2.2H

employs both N–H and O–H hydrogen bonds to activate trans-β-nitrostyrene for

nucleophilic attack by N-methylindole.

Scheme 2.4. Synthesis of control compound 2.6.

In an analogous fashion to the N-methylated pyridinium ions, the reaction rate data for

the N-protonated catalysts correlate with the IR vibrational frequency changes (Δυ) in the

N–H and O–H stretching modes. Neither λmax nor the 1:1 equilibrium binding constants

from the UV-vis titration experiments with 2.1, however, are good measures of the catalyst

activities. This break-down in the latter approach presumably is related to the higher-order

binding obtained with 2.2H and 2.4H. A plot of the logarithm of the experimental reaction

rate constants versus the computed G4 gas-phase acidities of the pyridinium ions provides

a reasonable linear correlation for all nine catalysts listed in Table 2.3 (Figure 2.6) even

55

though these compounds include N–H, O–H, and C–H hydrogen bond donors and the

counteranion is not accounted for in the calculations.

Figure 2.6. Logarithm of experimental rate constants vs computed G4 gas-phase

acidities. A linear least squares fit using all 9 catalysts in Table 2.3 gives ln k = –0.126

ΔG˚acid + 28.6, r2 = 0.875 whereas omission of 2.6 leads to ln k = –0.131 ΔG˚acid + 29.9,

r2 = 0.912 (not shown). Circles, diamonds, and triangles are used for 2.2Me–2.4Me (O–H

acids), 2.2H–2.4H, 2.5H, and 2.6 (N–H acids), and 2.5Me (C–H acids), respectively.

2.3 Conclusions

All three isomers of both the N-methylated and N-protonated hydroxypyridinium BArF4–

salts along with several reference compounds were investigated. DFT and G4 theory

computations, IR, UV-vis, and kinetic studies revealed the effects of changing the relative

position of the charged center to the ionization site, and the consequences of having one

(O–H) or two (O–H and N–H) hydrogen bond donating groups. Calculated gas-phase

acidities of the corresponding cations without their BArF4– counteranion were found to be

good predictors of the hydrogen bond donating abilities of these salts, and are linearly

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

4.0

200 210 220 230 240 250 260 270

ln k

(h–1)

ΔG˚acid (kcal mol–1)

2.2Me

2.5Me

2.4Me

2.3Me

2.2H

2.4H

2.6

2.5H, 2.3H

56

correlated with IR and UV-vis spectroscopic results and pseudo-first-order rate constants.

As a result, changes in the IR stretching frequencies of the O–H and N–H bonds in the

absence and presence of a hydrogen bond acceptor (Δυ) are reliable indicators of their

relative reactivity orders (i.e., O–H acids and separately N–H acids). In a similar manner,

1:1 equilibrium association constants obtained by UV-vis monitored titrations with a

colorimetric sensor (2.1) are good measures of the catalytic abilities of O–H (2.3Me,

2.4Me), N–H (2.5H, 2.3H, 2.4H) and C–H (2.5Me) Brønsted acids. This correlation breaks

down, however, for 2.2Me and 2.2H, both of which failed to give an isosbestic point and

were found to associate with two molecules of 2.1 (i.e., 2:1 binding).

Alkyl pyridinium ions with the charge center meta to the ionization site have been the

most widely employed charge-enhanced structures to come from our laboratory. These

species avoid introducing an additional O–H or N–H hydrogen bond donating site or

resonance delocalization effects. The latter interactions as reflected by comparisons of

2.2Me and 2.4Me relative to 2.3Me were found to lead to catalysts that are several times

more reactive in the Friedel-Crafts alkylation of N-methylindole with trans-β-nitrostyrene.

Introduction of the charged center by protonation leads to more acidic compounds, alters

the interaction site with the substrate, and affords modestly more active catalysts. The one

exception is 2.2H, which due to the ortho arrangement of its two acidic sites presumably

leads to bidentate activation, and resulted in a significantly larger rate enhancement. This

type of structural modification can lead to more rigid complexes and transition state

structures providing a means for more closely mimicking enzymes and designing more

reactive charge-activated catalysts.

57

2.4 Experimental

General. All reaction glassware (vials, NMR tubes, flasks) and stir bars were dried in an

oven (120 °C) for at least 16 h, and glass syringes and volumetric flasks were stored in a

vacuum desiccator over Drierite for at least 16 h. Alumina (neutral, Brockman I, standard

grade, 150 mesh, 58 Å) and 3 Å molecular sieves were activated at 300 °C for at least 24

h. Calcium chloride was obtained from Fischer Scientific and was dried at 300 °C for at

least 30 min (note: after 24 h at this temperature, the CaCl2 becomes tan and the use of

this discolored material led to poor results).

Anhydrous acetonitrile and iodomethane were obtained from Acros Organics and used

without further purification. 1,2-Dichloroethane (DCE) was purchased from Fischer

Scientific and was dried with a column of activated alumina and stored over 3 Å molecular

sieves under inert atmosphere for at least 24 h prior to use. N-Methylindole was used as

received from Alfa Aesar. Concentrated HCl (37%) was obtained from VWR International.

Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (NaBArF4) was obtained as a 2.5

hydrate (based on its 1H NMR spectrum) from AK Scientific. The water was removed by

dissolving the material in anhydrous methanol (2 g in 2 mL) and running the light-yellow

mixture through two pipets of activated alumina (1.25 g/pipet, each pipet was rinsed with

an additional 2 mL of methanol) and then through a 0.45 μm syringe filter. The solvent

was removed with a rotary evaporator and the remaining colorless solid was ground into

a fine powder and heated at 150 °C at 0.1 torr for at least 16 h35 in a glovebox (less than

0.06 H2O remained based upon the 1H NMR spectrum). N-Methyl-2-pyridone was

acquired from ArkPharm, Inc. as a dark brown oil that was dissolved in anhydrous ethyl

acetate, passed through a column of activated alumina (1.25 g), and concentrated to

58

afford a light-yellow oil. In a similar manner, 2-methoxypyridine (Oakwood Chemical) was

dried with an activated alumina column in anhydrous CH2Cl2.

All other chemicals and anhydrous solvents were supplied by Sigma-Aldrich and were

used as received unless described below. Pentane was stored over 3 Å molecular sieves

under argon for 24 h prior to use. Pyridine was dried with a short column of activated

alumina and stored over 3 Å molecular sieves under inert atmosphere for 2 days prior to

use.36 2- and 3-Hydroxypyridines were dried by dissolving 300 mg samples in 2 mL of

anhydrous methanol and passing the yellow mixture through a Pasteur pipet ¾ full of

activated alumina (~1.25 g). After rinsing the column with additional solvent (2 mL), the

colorless solution was concentrated with a rotary evaporator and then a mechanical pump

(0.1 torr), and the remaining white solid was stored in a glovebox. 4-Hydroxypyrdine was

dried in a similar manner to its isomers but was melted at 150 °C while under reduced

pressure (0.1 torr) for 5 min to remove any residual water (30 min under these conditions

led to discoloration and presumed decomposition).

Deuterated solvents came from Cambridge Isotope Laboratories and were stored over

3 Å molecular sieves for at least 24 h prior to use. Bruker Avance III HD 400 or 500 MHz

instruments were used to collect 1H, 13C, and 19F NMR spectra. All chemical shifts are

reported in ppm (δ) and 1H and 13C spectral data are referenced as follows: δ 5.32 and

54.0 (CD2Cl2); 1.94 and 118.3 (CD3CN); 2.50 and 39.5 (d6-DMSO). Fluorobenzene was

used as an internal standard for all 19F spectra (δ -113.78 in CD2Cl2; -114.81 in CD3CN).37

Thin layer chromatography was carried out with Macherey-Nagel precoated polyester

sheets (0.2 mm alumina with a fluorescent indicator) and visualized using a UV lamp.

Purification by MPLC was carried out with a CombiFlash® Rf automated flash

chromatography system from Teledyne Isco. Inc. on alumina (neutral, Brockman I,

59

standard grade, 150 mesh, 58 Å) columns. Uncorrected melting points were observed with

a Thomas Hoover Uni-Melt apparatus in unsealed capillaries. FT-IR data for

characterization were collected with a Thermo Scientific Nicolet iS5 spectrometer with an

iD5 ATR source and solution measurements were observed with a liquid cell (1.0 mm path

length) with NaCl windows. In all cases, ~5 mM phenol solutions were made in both dry

CD2Cl2 and dry 1% CD3CN/CD2Cl2 (v:v).9 Backgrounds of the solvent mixtures were used

to correct the corresponding spectra. Between each run, the cell was rinsed with CH2Cl2

and then purged with a flow of N2 for 10 min. High resolution electrospray ionization mass

spectra (HRMS-ESI) were obtained in methanol with a Bruker ESI-BioTOF instrument,

and tetramethylammonium and tetraethylammonium salts were used as mass calibrants.

Due to the low masses of the protonated salts (~96 m/z), protonated 2,6-lutidine was used

as a third calibration point. UV spectra were collected with a Lambda XLS spectrometer

from CH2Cl2 solutions in a 10 mm quartz cell that was sealed with a PTFE septum.

N-Methyl-4-pyridone.38 In a 25 mL round-bottomed flask fitted with a reflux condenser,

4-hydroxypyridine (200 mg, 2.10 mmol) and toluene (5 mL) were stirred and the

atmosphere was purged with argon for 15 min. Iodomethane (700 μL, 1.60 g, 11.2 mmol)

was then added in one portion by syringe and the resulting mixture was refluxed overnight.

Upon cooling to room temperature an orange precipitate and a light-yellow supernatant

remained. Hexanes (15 mL) were added to the suspension and the solid was isolated via

vacuum filtration. The collected material (~460 mg) was placed in a 6-dram vial, dissolved

in methanol (5 mL), and K2CO3 (300 mg, 2.17 mmol) was added with vigorous stirring.

After 2 h the reaction mixture was filtered, and the solid material was rinsed with 5 mL of

methanol. Removal of the solvent under reduce pressure afforded a yellow oily solid which

was dissolved in 5 mL of CH2Cl2. A white precipitate was filtered away and the light-yellow

60

filtrate was concentrated with a rotary evaporator to give 146 mg of an oily solid.

Purification of this material by column chromatography on alumina with 95/5

MeOH/CH2Cl2 (Rf = 0.3) afforded 104 mg (45%) of a colorless powder (mp 93 – 96 °C)

that was stored in a glovebox. 1H NMR (500 MHz, CD2Cl2) δ 7.23 (d, J = 7.2 Hz, 2H), 6.20

(d, J = 7.3 Hz, 2H), 3.58 (s, 3H). 13C NMR (125 MHz, CD2Cl2) δ 178.5, 141.1, 118.8, 43.9.

IR (ATR source) 1674, 1637, 1555 cm–1.

N-Methyl-3-hydroxypyridinium iodide. In a 25 mL round-bottomed flask fitted with a

reflux condenser, 3-hydroxypyridine (300 mg, 3.15 mmol) and acetonitrile (6 mL) were

stirred and the atmosphere was purged with argon for 10 min. Iodomethane (200 μL, 456

mg, 3.21 mmol) was rapidly added and the resulting solution was refluxed overnight. Upon

cooling to room temperature, the reaction mixture was concentrated with a rotary

evaporator and subsequently dissolved in 1 mL of anhydrous methanol. Dropwise addition

of the yellow material into 20 mL of anhydrous ethyl acetate in a 6-dram vial with vigorous

stirring under an inert atmosphere afforded a white precipitate. The yellow supernatant

was removed via syringe and the solid residue was washed with ethyl acetate in 10 mL

portions until the solvent became colorless. A rotary evaporator followed by a mechanical

pump (0.1 torr) were used to dry the product and 668 mg (89%) of an off-white fluffy solid

(mp 112 – 113 °C) was obtained. This material was stored in a glovebox. 1H NMR (500

MHz, CD3CN) δ 9.64 (OH, s, 1H), 8.50 (s, 1H), 8.24-8.23 (m, 2H), 7.81 (t, J = 7.8 Hz, 1H),

4.25 (s, 3H). 13C NMR (125 MHz, CD3CN) δ 157.6, 137.7, 134.7, 132.6, 129.2, 49.4. IR

(ATR source) 2963, 1581, 1506, 1492 cm–1. HRMS-ESI: calcd for C6H8NO (M – I–)+

110.0606, found 110.0586.

N-Methyl-3-hydroxypyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate

(2.3Me). In a 6-dram vial under argon, N-methyl-3-hydroxypyridinium iodide (31.9 mg,

61

0.135 mmol) and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (132 mg, 0.148

mmol) were added to 3 mL of anhydrous CH2Cl2 and vigorously stirred overnight. A white

precipitate was filtered with a 0.45 μm syringe filter and then washed with 2 mL of

additional CH2Cl2. The combined liquid material was concentrated with a rotary evaporator

and the resulting solid residue was dissolved in 2 mL of CH2Cl2. This solution was added

dropwise to 15 mL of anhydrous pentane in a 6-dram vial with stirring. A white solid formed

immediately and was allowed to settle to the bottom of the vial before the supernatant was

removed via syringe. The solid product was resuspended in 15 mL of pentane, collected

by vacuum filtration, and washed with 15 mL of pentane. It was then dissolved in 4 mL of

CH2Cl2, dried over MgSO4, and concentrated under reduced pressure to afford 82.6 mg

(63%) of a white solid (mp 179 – 180 °C). 1H NMR (500 MHz, CD2Cl2) δ 8.05 (s, 1H), 8.01

(d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.81-7.80 (m, 1H), 7.76 (s, 8H), 7.59 (s, 4H)

6.39 (OH, s, 1H), 4.26 (s, 3H). 13C NMR (125 MHz, d6-DMSO) δ 161.0 (q, 1JB-C = 50.0 Hz),

156.7, 136.4, 134.1, 133.8, 130.9, 128.5 (qq, 3JB-C = 2.7 Hz and 2JF-C = 31.6 Hz), 128.3,

124.0 (q, 1JF-C = 273 Hz), 117.7 (sept, 3JF-C = 4.1 Hz),39 47.8. 19F (376 MHz, CD2Cl2) δ -

62.6. IR (ATR source) 3593, 3510, 1611, 1598, 1516, 1354, 1275, 1104 cm–1. HRMS-ESI:

calcd for C6H8NO (M – C32H12BF24–)+ 110.0606, found 110.0583.

N-Methyl-2-hydroxypyridinium trifluoromethanesulfonate.40 In a 6-dram vial under

inert atmosphere, N-methyl-2-pyridone (100 μL, 111 mg, 1.02 mmol) was dissolved in 1

mL of anhydrous CH2Cl2. Neat trifluoromethanesulfonic acid (90 μL, 153 mg, 1.02 mmol)

was then added dropwise over 2-3 min at room temperature. A white precipitate was

observed after 10 min and the suspension was stirred for a total of 1 h. The reaction

mixture was diluted with 10 mL of pentane and the supernatant was removed via syringe.

The solid residue was washed twice with 10 mL of pentane, and then dried with a rotary

62

evaporator followed by a mechanical pump to afford 252 mg (95%) of a shiny, colorless

solid (mp 109 – 110 ºC) that was stored in a glovebox. 1H NMR (500 MHz, CD3CN) δ

12.05 (bs, OH, 1H), 8.20 (t, J = 8.1 Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.43 (d, J = 8.7 Hz,

1H), 7.29 (t, J = 6.9 Hz, 1H), 3.91 (s, 3H). 13C NMR (125 MHz, CD3CN) δ 161.1, 147.9,

143.2, 121.5 (q, 1JF-C = 319 Hz), 118.7, 115.3, 41.6. 19F (376 MHz, CD3CN) δ -79.4. IR

(ATR source) 2932, 1644, 1601, 1520, 1287, 1217, 1156, 1023 cm–1. HRMS-ESI: calcd

for C6H8NO (M – CF3SO3–)+ 110.0606, found 110.0581.


(2.2Me). In a 6-dram vial, N-methyl-2-hydroxypyridinium trifluoromethanesulfonate (25.9

mg, 0.100 mmol) and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (99.9 mg,

0.113 mmol) were added and the atmosphere was purged with argon. Anhydrous CH2Cl2

(3 mL) was then added and the resulting suspension was vigorously stirred for 5.5 h. The

reaction mixture was filtered through a 0.45 μm syringe filter and then washed with 2 mL

of additional CH2Cl2. The solvent was removed with a rotary evaporator and the solid

reside was dissolved in 1 mL of CH2Cl2 and the filtration procedure was repeated. Further

drying was performed with a mechanical pump to afford 96.2 mg (99%) of a colorless solid

(mp 105 – 106 ºC). 1H NMR (500 MHz, CD2Cl2) δ 11.62 (bs, OH, 1H), 8.15 (dt, J = 8.1 and

1.4 Hz, 1H), 7.93 (dd, J = 6.6 and 1.3 Hz, 1H), 7.73 (s, 8H), 7.56 (s, 4H), 7.28 (m, 2H),

3.97 (s, 3H). 13C NMR (125 MHz, CD2Cl2) δ 162.3 (q, 1JB-C = 49.5 Hz), 161.0, 147.6, 141.6,

135.4, 129.5 (qq, 3JB-C = 2.7 Hz and 2JF-C = 31.6 Hz), 125.2 (q, 1JF-C = 273 Hz), 118.4,

118.1 (sept, 3JF-C = 4.1 Hz),41 115.5, 41.7. 19F (376 MHz, CD2Cl2) δ -62.7. IR (ATR source)

3695, 3617, 1646, 1606, 1521, 1353, 1273, 1105 cm–1. HRMS-ESI: calcd for C6H8NO (M

– C32H12BF24–)+ 110.0606, found 110.0587.

63

4-Hydroxypyridinium trifluoromethanesulfonate. In a 6-dram vial, 4-hydroxypyridine

(52.5 mg, 0.552 mmol) was suspended in 1 mL of anhydrous acetonitrile and the

atmosphere was purged with argon for 15 min. Neat trifluoromethanesulfonic acid (100

μL, 170 mg, 1.13 mmol) was then added dropwise over 2-3 min at room temperature

resulting in a colorless clear solution that was stirred for an additional 30 min. The reaction

mixture was diluted with 10 mL of anhydrous diethyl ether and then 10 mL of pentane was

added to form a white precipitate. The supernatant was removed by syringe and the solid

residue was washed twice with 10 mL of pentane. The product was dried on a rotary

evaporator followed by a mechanical pump at 110 ºC for 4 h to afford 101 mg (75%) of a

light tan solid (mp 111 – 113 ºC) which was stored in a glovebox. 1H NMR (500 MHz,

CD3CN) δ 12.30 (bt, NH, JN-H = 56.0 Hz, 1H), 10.78 (bs, OH, 1H), 8.39 (d, J = 7.3 Hz, 2H),

7.31 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CD3CN) δ 172.8, 143.7, 121.6 (q, 1JF-C = 319

Hz), 115.1. 19F (376 MHz, CD3CN) δ -79.4. IR (ATR source) 3245, 3101, 1648, 1612,

1513, 1271, 1249, 1211, 1190, 1171, 1024 cm–1. HRMS-ESI: calcd for C5H6NO (M –

CF3SO3–)+ 96.0449, found 96.0437.

4-Hydroxypyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.4H). In a 6-

dram vial, 4-hydroxypyridinium trifluoromethanesulfonate (20.5 mg, 0.0836 mmol) and

sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (85.0 mg, 0.0959 mmol) were added

and the atmosphere was purged with argon. Anhydrous CH2Cl2 (2 mL) was then added

and the resulting suspension was vigorously stirred for 4.5 h. The reaction mixture was

filtered through a 0.45 μm syringe filter and then washed with 2 mL of additional CH2Cl2.

The solvent was removed with a rotary evaporator and the solid reside was dissolved in 1

mL of CH2Cl2 and the filtration procedure was repeated. Further drying was performed

with a mechanical pump to afford 74.5 mg (93%) of a colorless solid (mp 162 – 164 ºC).

64

1H NMR (500 MHz, CD2Cl2) δ 10.82 (t, NH, JN-H = 68.0 Hz, 1H), 8.35 (t, J = 6.9 Hz, 2H),

8.26 (bs, OH, 1H), 7.73, (s, 8H), 7.57 (s, 4H), 7.37 (d, J = 6.4 Hz, 2H). 13C NMR (125 MHz,

CD2Cl2) δ 172.4, 162.3 (q, 1JB-C = 50.3 Hz), 142.7, 135.4, 129.5 (qq, 3JB-C = 2.5 Hz and 2JF-

C = 31.4 Hz), 125.2 (q, 1JF-C = 273 Hz), 118.1 (sept, 3JF-C = 3.8 Hz),41 116.1. 19F (376 MHz,

CD2Cl2) δ -62.6. IR (ATR source) 3555, 3488, 3403, 1649, 1608, 1519, 1354, 1274, 1114

cm–1. HRMS-ESI: calcd for C5H6NO (M – C32H12BF24–)+ 96.0449, found 96.0438.

N-Methylpyridinium iodide. Following a literature procedure,42 pyridine (200 μL, 196 mg,

2.48 mmol) was dissolved in 10 mL of acetonitrile under argon in a 25 mL round-bottomed

flask equipped with a reflux condenser. Iodomethane (600 μL, 1.37 g, 9.64 mmol) was

then added by syringe and the reaction mixture refluxed overnight. Upon cooling to room

temperature, the yellow solution was concentrated with a rotary evaporator. The remaining

solid residue was then dissolved in 3 mL of acetonitrile and added dropwise into stirring

anhydrous diethyl ether under argon (15 mL). A white precipitate formed and was allowed

to settle to the bottom before removing the yellow supernatant via syringe. The solid was

washed with additional diethyl ether until the supernatant was colorless (4 x 10 mL) and

then was dried on a rotary evaporator followed by a mechanical pump to afford 545 mg

(99%) of a light-yellow solid (mp 108 – 110 °C). 1H NMR (500 MHz, d6-DMSO) δ 9.00 (d,

J = 5.4 Hz, 2H), 8.59 (t, J = 7.8 Hz, 1H), 8.14 (t, 6.7 Hz, 2H), 4.37 (s, 3H). 13C NMR (125

MHz, d6-DMSO) δ 145.5, 145.0, 127.6, 48.0.

N-Methylpyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.5Me). In a 6-

dram vial under argon, N-methylpyridinium iodide (31.2 mg, 0.141 mmol) and sodium

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (134 mg, 0.151 mmol) were added to 3 mL

of anhydrous CH2Cl2 and vigorously stirred for 1 h. A white precipitate was filtered with a

0.45 μm syringe filter and then washed with 2 mL of additional CH2Cl2. The combined

65

liquid material was concentrated with a rotary evaporator and the resulting solid residue

was dissolved in 2 mL of CH2Cl2, dried over MgSO4, and filtered again. Removal of the

solvent under reduced pressured afforded 96.2 mg (71%) of a colorless solid (mp 205 –

206 ºC) that had spectra consistent with a previous report.43 1H NMR (400 MHz, CD2Cl2)

δ 8.52-8.47 (m, 3H), 8.03 (t, J = 7.0 Hz, 2H), 7.73 (s, 8H), 7.56 (s, 4H), 4.37 (s, 3H). 13C

NMR (125 MHz, CD2Cl2) δ 162.4 (q, 1JB-C = 50.0 Hz), 147.0, 144.8, 135.4, 129.7, 129.5

(qq, 3JB-C = 2.7 Hz and 2JF-C = 31.6 Hz), 125.2 (q, 1JF-C = 273 Hz), 118.1 (sept, 3JF-C = 4.1

Hz), 49.7. 19F (376 MHz, CD2Cl2) δ -62.7.

Description of HCl gas apparatus.23

A picture of the reaction setup is given in Figure S1. An argon line was connected to

the top of an addition funnel (A) where concentrated HCl (1.0 – 2.0 mL) was stored prior

to its slow dropwise addition onto CaCl2 (1 g for every 1 mL of conc. HCl) in a 3-necked

round-bottomed flask (B). A small drying tube containing 0.5 – 1.0 g of additional CaCl2

(C) was used to further dry the HCl prior to entering the 6-dram reaction vial I via a 4”

needle (D) that could be inserted into the reaction medium; bubbling should be visible

when an argon flow is applied to the system. The effluent was then passed through a

neutralization column (F) filled with NaOH pellets to scavenge any residual HCl. Finally,

an oil-containing bubbler (G) was connected to the end of the apparatus and was useful

for identifying leaks and establishing suitable HCl flows.

General one-pot protonation and anion exchange procedure.

In a 6-dram vial, the starting pyridine or pyridone (1.0 eq.), NaBArF4 (1.0 – 1.2 eq.),

and a stir bar were placed. This reaction vessel was connected to the HCl generation

apparatus (Figure S1) and the entire system was purged for 5 min with argon. The desired

solvent was then introduced and the resulting suspension was stirred for an additional 5

66

min. Insertion of the 4” needle into the liquid medium (bubbling should be observed) was

followed by charging the addition funnel with concentrated HCl and its subsequent slow

dropwise addition onto the CaCl2. Bubbling in the 3-necked round-bottomed flask was

observed immediately and after 2-3 min, the suspension in the 6-dram vial became less

cloudy but did not clear up entirely. Upon completion of the HCl generation (no further

bubbling in the 3-necked flask), the reaction mixture was stirred for an additional 5 min

before it was passed through a 0.45 μm PTFE syringe filter which was then washed with

2 mL of the reaction solvent (DCE or CH2Cl2). Removal of the volatiles under reduced

pressure afforded a solid residue that was dissolved in CH2Cl2 and the filtration procedure

was repeated. Thereafter, the product was dried under high vacuum (0.1 torr) for at least

6 h and then it was stored in a glovebox.

Pyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.5H).44 Pyridine (18.0 μL,

17.7 mg, 0.223 mmol) and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (202 mg,

0.228 mmol) in 2 mL of CH2Cl2 were used. Following the general procedure led to 200 mg

(95%) of a white solid (mp 194 – 196 °C). 1H NMR (500 MHz, CD2Cl2) δ 12.25 (bs, 1H),

8.69-8.64 (m, 3H),45 8.13 (t, J = 7.0 Hz, 2H), 7.73 (s, 8H), 7.57 (s, 4H). 13C NMR (125

MHz, CD2Cl2) δ 162.3 (q, 1JB-C = 49.9 Hz), 149.9, 141.4, 135.4, 129.5 (qq, 3JB-C = 3.0 Hz

and 2JF-C = 31.2 Hz), 129.4, 125.2 (q, 1JF-C = 272 Hz), 118.1 (sept, 3JF-C = 4.0 Hz).41 19F

(376 MHz, CD2Cl2) δ -62.6. IR (ATR source) 3379, 1609, 1541, 1354, 1274, 1115 cm–1.

3-Hydroxypyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.3H). 3-

Hydroxy-pyridine (15.1 mg, 0.159 mmol) and sodium tetrakis(3,5-

bis(trifluoromethyl)phenyl)borate (141 mg, 0.159 mmol) in 1.5 mL of CH2Cl2 were used.

Following the general procedure led to 137 mg (91%) of an off-white solid (mp 178 – 180

°C). 1H NMR (500 MHz, CD2Cl2) δ 11.61 (NH, tt, JN-H = 65.0 Hz and J = 7.2 Hz, 1H), 8.29-

67

8.27 (m, 2H), 8.14-8.12 (m, 1H), 8.00 (t, J = 7.4 Hz, 1H), 7.73 (s, 8H), 7.56 (s, 4H), 6.48

(s, OH, 1H). 13C NMR (125 MHz, d6-DMSO) δ 161.0 (q, 1JB-C = 49.5 Hz), 156.2, 134.1,

133.5, 131.5, 130.6, 128.5 (qq, 3JB-C = 2.9 Hz and 2JF-C = 31.5 Hz), 127.7, 124.0 (q, 1JF-C

= 273 Hz), 117.7 (sept, 3JF-C = 3.6 Hz).41 19F (376 MHz, CD2Cl2) δ -62.7. IR (ATR source)

3582, 3527, 3379, 1610, 1559, 1355, 1274, 1104 cm–1. HRMS-ESI: calcd for C5H6NO (M

– C32H12BF24–)+ 96.0449, found 96.0436.

2-Hydroxypyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.2H). 2-

Hydroxy-pyridine (11.9 mg, 0.125 mmol) and sodium tetrakis(3,5-


Following the general procedure led to 91.4 mg (76%) of a white powder (mp 113 – 115

°C). 1H NMR (500 MHz, CD2Cl2) δ 10.77 (NH, t, JN-H = 60 Hz, 1H), 8.86 (bs, OH, 1H), 8.40

(t, J = 7.8 Hz, 1H), 8.09 (bs, 1H), 7.73 (s, 8H), 7.56 (s, 4H), 7.50 (t, J = 7.0 Hz, 1H), 7.37

(d, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CD2Cl2) δ 162.3 (q, 1JB-C = 49.9 Hz), 161.9, 151.4,

137.4, 135.3, 129.5 (qq, 3JB-C = 3.0 Hz and 2JF-C = 31.4 Hz), 125.1 (q, 1JF-C = 273 Hz),

120.2, 118.1 (sept, 3JF-C = 4.0 Hz),41 115.4. 19F (376 MHz, CD2Cl2) δ -62.7. IR (ATR source)

3542, 3369, 1649, 1633, 1610, 1543, 1354, 1273, 1112 cm–1. HRMS-ESI: calcd for

C5H6NO (M – C32H12BF24–)+ 96.0449, found 96.0440.


(2.4Me). N-Methyl-4-pyridone (11.3 mg, 0.104 mmol) and sodium tetrakis(3,5-

bis(trifluoromethyl)phenyl)-borate (93.3 mg, 0.105 mmol) in 2 mL of DCE were used.

Following the general procedure led to 82.3 mg (82%) of a white powder (mp 148 – 150

°C); residual DCE was removed by redissolving the material in 1 mL of CH2Cl2 and

removing the solvent with a rotary evaporator (20 torr), and then repeating this process at

least 3 times. 1H NMR (500 MHz, CD2Cl2) δ 8.80 (OH, bs, 1H), 8.10 (d, J = 6.6 Hz, 2H),

68

7.73 (s, 8H), 7.56 (s, 4H), 7.25 (d, J = 6.5 Hz, 2H), 4.10 (s, 3H). 13C NMR (125 MHz,

CD2Cl2) δ 170.5, 162.3 (q, 1JB-C = 49.5 Hz), 146.1, 135.3, 129.5 (qq, 3JB-C = 3.2 Hz and 2JF-

C = 31.6 Hz), 125.1 (q, 1JF-C = 273 Hz), 118.1 (sept, 3JF-C = 4.1 Hz),41 116.4, 47.7. 19F (376

MHz, CD2Cl2) δ -62.7. IR (ATR source) 3562, 3495, 1649, 1610, 1533, 1502, 1353, 1272,

1104 cm–1. HRMS-ESI: calcd for C6H8NO (M – C32H12BF24–)+ 110.0606, found 110.0587.

2-Methoxypyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (2.6). 2-

Methoxypyridine (12.5 μL, 13.0 mg, 0.119 mmol) and sodium tetrakis(3,5-


Following the general procedure led to 112 mg (97%) of a white powder (mp 163 – 165

°C). 1H NMR (500 MHz, CD2Cl2) δ 8.46 (ddd, J = 9.2, 7.4, and 1.8 Hz, 1H), 8.10 (dd, J =

6.2 and 2.1 Hz, 1H), 7.73 (s, 8H), 7.56 (s, 4H), 7.49 (t, J = 6.8 Hz, 1H), 7.35 (d, J = 9.0

Hz, 1H), 4.21 (s, 3H), missing NH. 13C NMR (125 MHz, CD2Cl2) δ 162.3 (q, 1JB-C = 50.0

Hz), 161.2, 151.4, 138.4, 135.4, 129.5 (qq, 3JB-C = 3.2 Hz and 2JF-C = 31.6 Hz), 125.1 (q,

1JF-C = 273 Hz), 119.9, 118.1 (sept, 3JF-C = 4.1 Hz),41 111.3, 59.7. 19F (376 MHz, CD2Cl2)

δ -62.7. IR (ATR source) 3372, 1644, 16118, 1545, 1353, 1273, 1113 cm–1. HRMS-ESI:

calcd for C6H8NO (M – C32H12BF24–)+ 110.0606, found 110.0585.

General procedure for dimerization determinations with 1H NMR spectroscopy.

A solution of known concentration consisting of 2.3Me, 2.3H, 2.4H, and 2.6 was made

in CD2Cl2 and an aliquot (0.5 mL) was transferred into a 9” NMR tube. An initial spectrum

was obtained before additional CD2Cl2 (0.1-0.5 mL) was added and mixed by inverting the

NMR tube twice. Another spectrum was recorded and this process was repeated multiple

times before carrying out a non-linear fit of the data using the BindFit program (see below)

to obtain the corresponding dimerization constants.

69

General kinetic study procedure for the Friedel-Crafts reaction of N-methylindole

with trans-β-nitrostyrene.

In a 1 mL volumetric flask, 74.6 mg (0.500 mmol) of trans-β-nitrostyrene, 6.2 μL (6.5

mg, 0.050 mmol) of N-methylindole, and the catalyst (0.005 mmol) were added and

dissolved in CD2Cl2 to a total volume of 1 mL. The flask was stoppered, and inverted twice

to ensure good mixing, and then the entire contents were transferred to an NMR tube

which was capped and sealed with electrical tape. A 1H NMR spectrum was taken as soon

as possible (within 10 minutes of mixing) and when the sample was not in the NMR

spectrometer, it was submerged in a 27 °C water bath. Reaction conversions were

calculated using the signals at 6.47 and 5.20 – 4.96 ppm for N-methylindole and the

product, respectively, and a pseudo-first-order kinetic model was employed.

General procedure for UV titrations.8,10d

Solution preparation. In a 1 mL volumetric flask, 1.0-1.5 mg of the sensor was dissolved

in CH2Cl2 to the line in the glassware. In a 5 mL volumetric flask, 25 μL of the 1 mg/mL

sensor solution was added and then was diluted to the line with CH2Cl2 (solution A). In a

separate 5 mL volumetric flask containing 20 – 30 equivalents of the Brønsted acid,

another 25 μL of the 1 mg/mL sensor solution was added and diluted to the line with

CH2Cl2 (solution B).

Titration procedure. In a 10 mm cuvette with a screwcap top, 2 mL of solution A was added

and the vessel was sealed with a PTFE septum. After collecting the background of only

CH2Cl2, a spectrum of the free sensor from 300 – 950 nm was obtained and the λmax and

the absorbance value at λmax were recorded. Then an aliquot (10-15 μL) of solution B was

added by microsyringe to the cuvette which was then shaken for 15-20 seconds, and then

another spectrum was collected. The new λmax and its corresponding absorbance value

70

were recorded and cuvette was shaken again (15-20 seconds) and the spectrum was

recollected to ensure that λmax and the absorbance at λmax were invariant. If significant

changes were observed (greater than ± 1 for λmax or ± 0.010 for the absorbance), the

mixture was shaken again and another spectrum was collected until the data was

consistent (in general, no more than 4 repetitions were needed). Then another portion (10-

15 μL) of solution B was added and the collection procedure was repeated. As the titration

went along, the amount of titrant (solution B) could be increased (20 – 500 μL) until the

observed λmax and the absorbance value did not change after 2 consecutive additions.

Calculating the binding constants. Absorbance values from 4 different wavelengths and

the equivalents of Brønsted acid to sensor were used to calculate the binding constant

(K). The λmax of the free sensor (~500 nm) and of the bound complex, and wavelengths 30

nm above (~530 nm) and below those values were used in the analysis. These data points

were nonlinearly fit with the BindFit app (http://app.supramolecular.org/bindfit/) for 1:1, 1:2,

and 2:1 sensor to catalyst relationships to obtain the binding constants and the statistical

errors.

Computations

DFT (B3LYP/6-31G(2df,p), B3LYP/cc-pVDZ, B3LYP/cc-pVTZ//B3LYP/cc-pVDZ, M06-

2X/cc-pVDZ and M06-2X/cc-pVTZ//M06-2X/p-VDZ)46,47 and G4-theory19 computations

were carried out using Gaussian 16 at the Minnesota Supercomputer Institute for

Computational Chemistry or on a desktop MacIntosh computer with GaussView 6.48,49 All

structures were fully optimized and correspond to minima on the potential energy surface

(i.e., all of the vibrational frequencies correspond to positive values). Geometries, energies

and select vibrational frequencies are provided in the appendix.

71

Chapter 3: How Reliable Are Enantiomeric Excess Measurements Obtained

By Chiral HPLC?*

3.1 Introduction

Synthetic chemists routinely report quantitative results but the accuracy and

reproducibility (i.e., the precision) of the measurements typically are not provided. For

example, reaction yields, accurate mass determinations, chemical shifts, optical rotations,

and selectivities are rarely given with uncertainties or as ranges. In some cases there are

good reasons for these commonly accepted standards, but in others this can lead to

ambiguity and potential errors.1,2

One such quantity that our laboratory has begun to measure regularly and that is

almost invariably given as a single number is the enantiomeric excess (ee) or its

equivalent, the enantiomeric ratio (er).3-10 These values are most widely collected by high

performance liquid chromatography (HPLC) with a chiral column,11,12 and the reliability of

these measurements are sensitive to a variety of factors.13-16 The resolution of the peaks,

their elution order and their relative ratios have been shown to have a significant impact

on the reliability of the results.17-24 Despite these known issues, synthetic chemists have

largely ignored the intrinsic errors of this method and commonly do not report observed

absorbance values, experimental uncertainties or the most widely used descriptors for

peak separations (i.e., the selectivity factor (α)25 and resolution (Rs)26). This is a concern

when optimizing and evaluating reaction results because it is not always clear when a

change in ee or er represents an improvement toward a more selective transformation.27

* Reprinted (adapted) with permission from Payne, C.; Kass, S. R. How Reliable are Enantiomeric Excess Measurements Obtained by Chiral HPLC? ChemistrySelect 2020, 5, 1810-1817. Copyright (2020) Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.

72

For example, can one be confident that a 90% ee determination is reliably better than a

finding of 84% or 86% ee despite the fact that the first of these is usually viewed as

corresponding to excellent enantioselectivity whereas the latter two results are considered

to be only very good? Equivalently, is a 95:5 ratio meaningfully different from 92:8 or 93:7?

Given that experimental uncertainties typically are not provided even though ee and

er measurements are widely reported, it seemed worthwhile to examine the quality of data

collected by routine analyses with chiral HPLC. That is, how does a method that is

developed for the separation of a racemic mixture affect the precision and accuracy of an

observed value for an unknown sample that may have a completely different enantiomeric

composition? In this report, commercial samples of ibuprofen (3.1) with sample

concentrations that led to absorbance values between 0.02 and 2.0 for both the major and

minor enantiomers were used, and conditions leading to essentially baseline separation

of the two enantiomers in a racemic sample (1% overlap), near baseline separation (4%

overlap), and a poorer but still quite good resolution (17% overlap) were examined.28-30

These results should provide a practical guide to the accuracy and precision one can

expect when carrying out routine ee determinations by HPLC without the use of peak

deconvolution software, calibration curves, or dual detection methods.31


Ibuprofen was chosen for this study because its enantiomers can be purchased in high

enantiopurities, the optical rotation has been reported ((S)-3.1: [ɑ]D20 = +59˚ (c 2.0,

ethanol)),32 and it was known that the (R)- and (S)-isomers can be separated with a chiral

HPLC column. This was confirmed with a racemic sample, and near baseline separation

73

(i.e., 1% overlap) was achieved with a 90:10 hexanes/isopropanol (with 0.4% v/v NH4OAc)

solvent mixture and a flow rate (F) of 1.0 mL min-1 on a 250 mm x 4.6 mm Whelk-O1

column (Figure 3.1, solid line). Slightly overlapped peaks (4% overlap) were obtained

when the eluent was changed to a 82.5:17.5 hexanes/isopropanol ratio and F was reduced

to 0.8 mL min–1 (Figure 3.1, dashed line).

Figure 3.1. Chiral HPLC separations of 3.1 with 90:10 (solid line, 1% overlap) and

82.5:17.5 (dashed line, 4% overlap) hexanes/i-PrOH mixtures and 0.4% v/v NH4OAc on a

Whelk-O1 column.

Optical rotations of -58.15 ± 0.28˚ and +58.40 ± 0.10˚ were observed in absolute

ethanol at 20 ˚C for (R)- and (S)-ibuprofen, respectively.33 These results indicate that the

commercial samples were 98.6 ± 0.5% and 99.0 ± 0.2% ee in accord with the suppliers

provided specifications of ≥ 98% ee. Standards of varying enantiopurities were prepared

from these compounds and each sample was analyzed five times to reduce random errors

in the measurements. Based upon the UV-vis spectrum of 3.1 (Figure 3.2), seven different

0

200

400

600

800

1000

1200

1400

4.0 5.0 6.0 7.0 8.0

Ab

sorb

an

ce (

mA

U)

Time (min)

R

S

74

wavelengths (220, 225, 230, 235, 240, 254, and 262 nm) were selected to monitor the

chiral separations. These values represent wavelengths near the two absorption maxima

(222 and 264 nm) and the minimum between these features (248 nm), the most commonly

employed wavelength in HPLC studies (254 nm), and three spaced out locations along

the largest band in the spectrum.

Figure 3.2. UV-vis spectrum of ibuprofen from 210-300 nm obtained with a HPLC-

photodiode array detector. Open circles are at the seven wavelengths used to monitor all

of the chiral separations.

Post data collection parameters can play a critical role in the quantitative analysis of

the resulting HPLC chromatograms.34 General methods that do not involve peak

deconvolutions and that can be applied without knowing the enantiomeric composition

were employed as this is the situation typically encountered in a research laboratory when

carrying out routine analyses. In this regard, a vertical drop method was used to

differentiate and integrate all of the peaks in each chromatogram. No corrections for peak

asymmetry (i.e. tangent skimming)35 were introduced because this led to increased errors

given that the instrument software for our HPLC system cannot account for both peak

fronting and tailing at the same time. The peak width parameter for peak identification was

0

500

1000

1500

2000

210 220 230 240 250 260 270 280 290 300

Ab

sorb

an

ce (

mA

U)

Wavelength (nm)

75

set (0.20 min) for all chromatograms based on the HPLC software manual

recommendations.36 A universal parameter used by chromatographic instruments is the

slope sensitivity (or peak threshold) that sets the integration starting and end points, and

primarily addresses signal to noise issues.34 Thus, this criterion has a significant impact

on the observed measurements when analyses are monitored at wavelengths with low

absorbances or when small peaks are present (i.e., high enantiomeric compositions).37

This dependence was observed when the default setting for the universal slope sensitivity

(s = 5) was initially used, and the minor enantiomer was not detected at 254 nm under 1%

overlap conditions in samples with ees as low as 90% even though it can be seen by eye

in the chromatogram.37 A universal value of s = 0.01 was subsequently employed, but the

results were found to vary with the magnitude of this parameter and are wavelength

dependent.38 Therefore, a range of slope sensitivities were examined at the least

absorbing wavelength (254 nm) to assess its impact on the ee determination and the

detection of the minor enantiomer in the commercial samples of (R)- and (S)-3.1 (where

the signal to noise is the smallest in all of the standards). Values of 0.01-0.10 and 0.06-

0.22 led to invariant results for the enantiopure (R)- and (S)-samples,39 respectively and

s254 = 0.10 was selected for the analyses of the prepared standards. Since the effect of

this parameter is wavelength dependent, it was adjusted for the detection wavelength by

using the absorbance ratio as a scale factor (i.e., sx = 0.10 • Ax/A254).40 Default settings

were employed for the other integration parameters (baseline correction, peak to valley

ratio, and reference wavelength) since the results were insensitive to these values.

Five injections of each sample were used to obtain an averaged ee and reduce the

random error in the observed measurement. These results along with the standard

deviations as given by 2σ and the errors in the data (i.e., observed ee – calculated ee)

76

were obtained at all of the monitored wavelengths using the two enantiomeric separations

illustrated in Figure 3.1.41 The findings at 220 nm where the major enantiomer elutes first

and the best resolution in this study was used (1% overlap for a racemic sample) are given

in Table 3.1. Excellent accuracies (+0.4 - –0.2%) and reproducibilities (± 0.6%) were

obtained for samples with > 90% ee. This occurs because there is no overlap in the

chromatograms (see Figures S14-S18) when the (S)-enantiomer is < 5% of the mixture.

For the two samples between 75 and 90% ee, the (R)- and (S)-enantiomers start to overlap

(Figures S19-S20) and this leads to decreased precision without affecting the accuracy.

More equal enantiomeric amounts (i.e., < 60% ee) led to increased values for 2σ and

larger deviations from the true ees presumably because peak overlap disrupts the

integrator’s ability to consistently distinguish where the first feature ends and the second

one begins.

Table 3.1. Data collected at 220 nm under the most favorable separation conditions

(1% overlap) where the major (R) enantiomer eluted first.

calc ee (%)a obs ee (%)b error (%)c

98.6 99.0 ± 0.2 +0.4

96.8 96.6 ± 0.6 -0.2

94.8 94.6 ± 0.4 -0.2

92.8 92.8 ± 0.3 0.0

90.8 90.8 ± 0.3 0.0

88.8 88.8 ± 0.8 0.0

78.8 78.8 ± 2.0 0.0

58.8 57.9 ± 1.4 -0.9

38.8 39.5 ± 0.9 +0.7

19.2 20.1 ± 0.6 +0.9

aDetermined by optical rotation of commercial samples and varying amounts of their stock solutions (see the

appendix for more details). The (R)-enantiomer is in excess in each case. bThese values are averages of 5

injections with uncertainties corresponding to two standard deviations (i.e., 2σ). Error = obs ee - calc ee.

77

The same elution order with slightly poorer resolution in the chromatogram (i.e., 4%

overlap for a racemic mixture, see Fig. 3.1) is presented in Table 3.2. In this situation the

(S)-component in the commercial (R)-ibuprofen was not detected, and the 98.6% ee

sample was determined to be 100%. This result indicates that it can be difficult to

accurately measure compounds with high enantiopurities with this elution order when the

peaks in the racemic chromatogram slightly overlap.18,21,23 Moreover, the errors for the

same standards with ees between 78 and 97% increased from 0.0 - 0.2% to 0.6 - 1.0%.

In these cases the area of the (R)-enantiomer (i.e., the first peak) is underdetermined

leading to observed ee values that are too small. This systematic error is a result of the

vertical drop method and peak tailing.17,20,22 The reproducibility of the data also decreased

for the higher enantiopurity samples (> 88% ee) relative to the results in Table 3.1 but it

increased for the standards with more equal amounts of the two enantiomers.

Table 3.2. Data Collected at 220 nm Under Less Favorable Separation Conditions

(4% Overlap) Where the Major (R) Enantiomer Eluted First.


98.6 100d +1.4

96.8 95.9 ± 0.9 -0.9

94.8 93.9 ± 0.6 -0.9

92.8 92.3 ± 0.4 -0.5

90.8 89.9 ± 1.3 -0.9

88.8 88.0 ± 1.1 -0.8

78.8 78.0 ± 1.0 -0.8

58.8 56.7 ± 0.5 -2.1

38.8 38.2 ± 0.6 -0.6

19.2 18.9 ± 0.7 -0.3



injections with uncertainties corresponding to two standard deviations (i.e., 2σ). cError = obs ee - calc ee. dThe

minor (S) enantiomer was not detected.

78

Our data for when the elution order was reversed and the major enantiomer comes off

the column second using the conditions that led to the best resolution (i.e., 1% overlap in

a racemic sample) are summarized in Table 3.3. Excellent reproducibilities within ± 0.2%

and accuracies within +0.6% ee were obtained for the samples with large differences in

the enantiomeric ratios (i.e., ≥ 89.2% ee). The high level of precision (≤ 0.5%) was

maintained for the lower enantiopurity standards, but the error changed sign and led to ee

determinations that were 1 to 2% too small. This decrease in accuracy can be attributed

to overlapping peaks for the two enantiomers in the chromatograms when they are present

in more equal amounts (i.e., < 80% ee, see Figures S24-S27). In other words, it is difficult

to obtain very accurate results when two peaks intersect without addressing both tailing

and fronting of the overlapping signals.

Table 3.3. Observed results at 220 nm under the most favorable separation

conditions (1% overlap) where the major (S) enantiomer eluted second.


99.0 99.6 ± 0.1 +0.6

97.2 97.5 ± 0.2 +0.3

95.2 95.6 ± 0.2 +0.4

93.2 93.5 ± 0.1 +0.3

91.2 91.4 ± 0.1 +0.2

89.2 89.4 ± 0.2 +0.2

79.4 78.7 ± 0.2 -0.7

59.6 57.7 ± 0.3 -1.9

39.6 38.5 ± 0.3 -1.1

20.0 18.2 ± 0.5 -1.8

0.4 -1.0 ± 0.4d -1.4


appendix for more details). The (S)-enantiomer is in excess in each case. bThese values are averages of 5

injections with uncertainties corresponding to two standard deviations (i.e., 2σ). cError = obs ee - calc ee. dA

negative number is used because the (R)-enantiomer was found to be in excess.

79

Similar measurements with respect to the elution order and the monitored wavelength,

but with slightly poorer resolution (i.e., 4% overlap in a racemic sample) were carried out

and are summarized in Table 3.4. The reproducibilities of the results are similar to those

obtained with higher resolution (≤ ± 0.5%) and again the observed ee values are on

average 0.3 – 0.4% too large for the high enantiopurity standards (i.e., ≥ 89.2%). In

addition, the sign in the error changes once again when more equal amounts of the two

enantiomers are present (i.e., ≤ 79.4% ee), but its magnitude is reduced compared to the

data in Table 3.3. That is, the accuracy ranges from -0.7 – -1.9% compared to -0.4 –

-1.3% for the data in Tables 3.3 and 3.4, respectively. Apparently under the less favorable

separation conditions there is some fortuitous cancelation of errors due to peak tailing and

fronting.17

Table 3.4. Observed results at 220 nm under the less favorable separation

conditions (4% overlap) where the major (S) enantiomer eluted second.


99.0 99.5 ± 0.5 +0.5

97.2 97.4 ± 0.2 +0.2

95.2 95.6 ± 0.2 +0.4

93.2 93.6 ± 0.3 +0.4

91.2 91.6 ± 0.2 +0.4

89.2 89.5 ± 0.2 +0.3

79.4 79.0 ± 0.3 -0.4

59.6 58.3 ± 0.2 -1.3

39.6 39.1 ± 0.3 -0.5

20.0 19.3 ± 0.4 -0.7

0.4 0.0 ± 0.3 -0.4


appendix for more details). The (S)-enantiomer is in excess in each case. bThese values are averages of 5

injections with uncertainties corresponding to two standard deviations (i.e., 2σ). cError = obs ee - calc ee.

80

The results above reveal that routine HPLC analyses can be accurate and

reproducible with errors and experimental uncertainties of ≤ 2%. In most cases these

values are significantly smaller and for samples with ees of ≥ 80%, ± 1% or better were

generally observed. With few exceptions, errors in the measured values are as large or

larger than the uncertainties in the measurements, except for the overlap data where the

major enantiomer elutes off the column first under 1% overlap conditions (Table 3.1). The

standard deviations for both the 1 and 4% overlap data are also significantly larger when

the major component comes off the column first (in this case, (R)-ibuprofen). With the

latter resolution, the minor (S)-enantiomer was not observed in the most enantiopure (R)-

sample, the differences in the 89% and 91% ee standards are not statistically significant,

and the error bars for the 93, 95, and 97% ee samples nearly overlap (Figure 3.3, solid

lines). If only three injections are used to analyze the data (dotted lines),42 then one cannot

be confident that a 2% ee difference in values ranging from 89 to 97% are meaningfully

different.

Figure 3.3. Calculated versus observed ees (%) at 220 nm with 4% overlap in a racemic mixture. Filled circles and open triangles are for when the major enantiomer elutes first and second, respectively; in the latter case the data have been offset by 1.0% along the y-axis for clarity. Uncertainties are given by 2σ and are based on five measurements (solid lines), whereas dotted lines were used for at least one of the possible combinations using only three of the data points.

8687888990919293949596979899

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

ee

ca

lc (

%)

ee obs (%)

81

An increase in the separation between the two enantiomers in the HPLC

chromatogram illustrated in Figure 3.1 should afford data with excellent accuracy and

precision similar to the results given in Tables 3.1, 3.3 and 3.4 where the ee is ≥ 90%.

That is, measurements made under conditions where there is no peak overlap will be very

reliable.43 One would expect that a decrease in the resolution, however, leads to larger

errors and poorer reproducibility. This situation where there is more peak overlap but the

two enantiomers are still clearly resolved is sometimes encountered.30 Consequently, the

mobile phase was adjusted to a 72.5:27.5 hexanes/isopropanol (with 4% v/v NH4OAc)

mixture with F = 0.8 mL min–1 and this resulted in 17% overlap using a racemic mixture of

3.1 (Figure 3.4).28,29 These conditions, along with the same post data collection

parameters as before, were used to examine the commercial (R)- and (S)-ibuprofen

samples in addition to the 80, 90, and 95% ee standards for both enantiomers.

Figure 3.4. Separation of a racemic mixture of ibuprofen with a 72.5:27.5 hexanes/i-PrOH

mixture containing 0.4% v/v NH4OAc on a Whelk-O1 column as monitored at 220 nm.

0

200

400

600

800

1000

1200

3.8 4.8 5.8 6.8

Absorb

ance (

mA

U)

Time (min)

R S

82

When the major (R) enantiomer eluted off the column first, the minor component was

not observed in the ≥ 95% ee samples (Table 3.5). That is, the integrator did not record

the signal for the (S)-enantiomer under these conditions even when this feature can be

detected by the eye in the 95% ee sample (Figure S57).45 This led to an overestimation of

the ee whereas the other two standards led to underestimations of 3 and 4%17,18,20,22,24

The reproducibility of the latter two measurements is ± 1%, but the dominant error is the

inaccuracy of the observed result as is the case in Tables 3.2-3.4.

Table 3.5. Data collected at 220 nm under conditions leading to 17% peak overlap

in a racemic mixture where the major (R) enantiomer was first off the column.


98.6 100d +1.4

94.8 100d +5.2

88.8 85.8 ± 0.8 -3.0

78.8 74.9 ± 1.0 -3.9




minor (S) enantiomer was not detected.

When the elution order was reversed using these more poorly resolved conditions, the

minor (R) enantiomer was not observed in the commercial sample of (S)-ibuprofen (Table

3.6). This result along with the findings in Table 3.5 indicate that high enantiopurity

determinations are challenging to quantify when the two enantiomers overlap somewhat

in the racemic HPLC chromatogram (i.e., as in Figure 3.4) regardless of the elution order.18

If the major enantiomer comes off the column first, then almost any peak overlap can be

problematic when trying to measure small amounts of a minor enantiomer (i.e., ≥ 98% ee,

see Table 3.2).21,23 The reproducibility of the data in Table 3.6 is excellent (± 0.3% or

83

better), but there is a systematic error in the observed ees leading to values that are

uniformly too large.17,18,20,22,24

Table 3.6. Data collected at 220 nm under conditions leading to 17% peak overlap

in a racemic mixture where the major (S) enantiomer eluted second off the column.


99.0 100d +1.0

95.2 96.6 ± 0.1 +1.4

89.2 91.1 ± 0.1 +1.9

79.4 81.8 ± 0.3 +2.4




minor (R) enantiomer was not detected.

Six additional wavelengths (225, 230, 235, 240, 254, and 262 nm) were monitored for

all of the samples noted above. A small chemical impurity was observed in the standards

enriched with (R)-ibuprofen at 240, 254, and 262 nm (Figure 3.5) but not at the other

wavelengths. This is due to the commercial sample which was supplied with a 99.5%

chemical purity; this determination was based upon an HPLC trace and a 1H NMR

spectrum (both provided by the supplier) that is consistent with a high purity compound.

The observed shouldering was not present in the (S)-ibuprofen samples at any wavelength

and consequently similar results with regard to accuracy and precision to those in Tables

3.1-3.6 obtained at 220 nm were found at 225, 230, and 235 nm. Less reliable results

were obtained when the (R)-enantiomer was in excess and the other three wavelengths

(240, 254, and 262 nm) were used to monitor the chromatograms.41 Since molar

absorptivities of different compounds can vary by orders of magnitude45 and are

wavelength dependent,47 relative peak areas of non-enantiomeric species in HPLC

chromatograms are not reliable measures of mixture compositions in the absence of

84

additional data (e.g., calibration curves). As a result, impurities are a source of concern

even for samples with high chemical purity (i.e., ≥ 98 or 99%). Consequently, multiple

wavelengths should be monitored with instruments having this capability, and we

recommend that this become standard operating procedure. The standard deviations in

the resulting data (i.e., the random errors in the measurements) can be reduced and

increased reproducibilities can be obtained by averaging the determinations obtained at

multiple wavelengths (see Table S28). This is generally unwarranted, however, because

the systematic errors tend to limit the accuracy of the data and are as large or larger than

the experimental uncertainties as given by 2σ at one wavelength for five repeat

measurements.

Figure 3.5. HPLC chromatographs of a 95 (R) : 5 (S) mixture monitored at 220 (top) and

254 nm (bottom) using favorable separation conditions (i.e., 1% overlap in a racemic

mixture).

R S

R S

85

The resolution (Rs) for each chromatogram in this work was calculated and found to

vary with the enantiomeric composition. A plot of Rs versus the uncertainty (2σ) in the ee

(Figure 3.6) falls into three categories: Rs = ~2.44, 1.76 and 1.22 or 1, 4 and 17% overlap

in a racemic mixture, respectively.47 More precise data are not obtained when Rs is larger,

in fact the opposite is observed for the 1 and 4% overlap data. These counterintuitive

results are due to a number of factors (e.g., the use of the vertical drop method), but are

indicative that more precise measurements are obtained when the major enantiomer

comes off the column after the less abundant enantiomer (i.e., compare the filled and open

symbols in Fig. 3.6). In terms of accuracy, no relationship with Rs was observed but not

surprisingly, the 17% overlap data have the largest errors.

Figure 3.6. A comparison of the measured uncertainty in the ee (2σ) versus the

chromatogram resolution (Rs). Triangles, squares, and circles represent the 17, 4, and 1%

data, respectively. Filled and unfilled symbols are for when major enantiomer elutes off

the column first and second, respectively.

3.3 Conclusions

In this report, we examined the reliability of ee determinations over the full range of

possibilities for high purity (R)- and (S)-ibuprofen samples (i.e., racemic to enantiopure

0.0

0.5

1.0

1.5

2.0

2.5

1.00 1.50 2.00 2.50 3.00

2σ

(±%

)

Rs

86

standards) by chiral HPLC with different peak resolutions and elution orders. Default

instrument parameters were employed for the post data collection analysis except for the

slope sensitivity since it has a significant impact on the resulting ee determinations; the

default value led to large errors (i.e., under and over determinations ranging from -3.0%

to +11.2%, respectively; see Table S23), and is wavelength dependent. This is especially

an issue when a low signal to noise ratio is encountered as is often the case for high ee

samples. Multiple wavelength detection also revealed a co-eluting impurity despite using

high purity (≥ 99%) compounds, providing incentive to observe the entire UV-vis spectrum

or as many wavelengths as possible when more than one wavelength can be monitored.

Additionally, five sample injections lead to significantly less variability in the data than

when only three are employed, and the differences can be considerable.

The aim of this work was to address how a method that was created for the separation

of a racemic mixture affected the reliabilities of measurements for samples that span the

full range of possible ees. Elution order and the degree of peak overlap in the

chromatogram play a critical role and enable us to answer the question posed in the

introduction. That is, can one be sure that a 90% ee determination is better than an 84 or

86% ee measurement? The answer depends on the chromatogram resolution, elution

order, and the number of replicate measurements carried out. If baseline separation is

achieved, then one can reliably differentiate an ee of 90% from a value of 84 or 86%.

Under less than ideal conditions (e.g., 4% overlap in a racemic mixture), and particularly

if only three measurements are carried out, then the answer may be no. Given the different

factors that affect measurement reliability, we recommend practicing synthetic chemists

follow the general guidelines given in Table 3.7 when carrying out routine chiral HPLC

analyses.

87

Table 3.7. General enantiomeric excess measurement guide for chiral HPLC.

Step Procedure

1 – racemic sample method development

(a) Record a UV-vis spectrum of the sample and decide which wavelength(s) (λ) to monitor for the analyses. A minimum of 3 well-spaced out λs should be used, if possible; this may need to be done sequentially if only one λ can be monitored at a time. Consider λmax, ½ λmax, and a wavelength with low intensity. Also, employ a reference λ to minimize baseline drift if this instrumental feature is available, but be sure the sample does not absorb at this λ.a (b) Use similar sample concentrations for all analyses (e.g., 1 mg mL–1) and be sure all of the observed absorbances are in the linear range of the detector (e.g., between 0.02 and 2.0).b

(c) Optimize separation conditions for both enantiomers and any additional species (e.g., column selection, mobile phase, and flow rate). (d) Calculate the percent overlap; height of the valley between the enantiomers above the baseline times 100 divided by the height of the first enantiomer peak. i. If < 1%, the method should provide reliable results (barring an overlapping impurity) regardless of the elution order. Proceed to step 2. ii. If 1-14%, the elution order will impact the measurement’s accuracy and reproducibility. One may wish to attempt to obtain better resolution, and only should proceed to step 2 with caution. iii. If ≥ 15%, new chromatographic conditions or a different column should be used.

2 – ee assessment

(a) Inject a sample of interest using the conditions from step 1. (b) Inspect the peaks of interest for impurities (e.g., shouldering). If observed, further purification or another column is warranted. (c) Note the elution order (i.e., is the major enantiomer first or second?) i. If < 1% overlap, the results should be independent of the of elution order. Proceed to step 3. ii. If 1-14% overlap and the major enantiomer elutes first, the results will be less accurate and less precise. Either improve the chromatography (i.e., return to step 1) or proceed to step 3 with this limitation. If the minor enantiomer elutes first, proceed to step 3. In either case, high ee values (≥ 95%) may be less accurate.

3 – post-collection analysis

(a) Determine a range of slope sensitivities where the ee is invariant using the employed wavelength with the smallest absorbance and adopt the largest value (si); this parameter deals mostly with signal to noise issues and is most sensitive for high ee samples. Alternatively, if available, use the "auto integration" feature, where the software adjusts integration parameters for each chromatogram. (b) Scale the slope sensitivity value for other wavelengths using their absorbance ratios (i.e. sx = si x Ax/Ai). (c) Calculate the ee (or er) at multiple wavelengths. i. If the values are the same, proceed to step 4. ii. If different values are obtained, purify the sample further or change the separation conditions (i.e., return to step 1c).

4 – final ee determination

Carry out 5 injections of the sample of interest and report the retention times, elution order, peak overlap percent, absorbance values, and averaged ee value along with its standard deviation.

aIf a UV-vis spectrum is not recorded, use well spaced out wavelengths such as 220, 235, and 250, and do not employ a reference wavelength to minimize noise and reduce baseline drift. bAbsorbance values should not be too large for the major enantiomer or too small for the minor component.

88

3.4 Experimental

General Information: Racemic and (S)-ibuprofen (100% chemical purity), and HPLC

grade hexanes and isopropanol were purchased from Sigma-Aldrich. (R)-Ibuprofen

(99.5% chemical purity) was acquired from Ark Pharm, Inc., and ammonium acetate was

obtained from Fischer Scientific. Absolute ethanol was provided by Decon Laboratories,

Inc. and was dried by running the solvent through a column of activated alumina (300 °C

for 24 hours) and was stored over dried 3Å molecular sieves under argon. Micropipettes

(20-200 μL and 100-1000 μL) were calibrated using HPLC grade hexanes (see the

appendix for additional details). Ammonium acetate (4.68 g, d = 1.17 g mL-1) was dissolved

in isopropanol (996 mL) to prepare a 0.4% v/v solution used in the mobile phase.

Preparation of Standards: Stock solutions of both ibuprofen enantiomers with

concentrations of 1 mg mL-1 were prepared by dissolving 25 mg of (R)- or (S)-3.1 with

hexanes in a 25 mL volumetric flask. A stir bar was then added and the solution was mixed

vigorously for 10 min to ensure homogeneity. Aliquots of these stock solutions were

transferred into HPLC vials via micropipettes to afford a series of 1 mL standards of

varying enantiopurities (see the appendix for further details).

HPLC Analyses: All samples were injected five times on a liquid chromatograph, which

consisted of an isocratic pump and quaternary pump, a standard autosampler, and a

photodiode array detector. This instrumentation was controlled with OpenLAB CDS

Chemstation Edition software and a (S,S)-Whelk-O1 (5 μm, 250 mm x 4.6 mm) column

was used.

Separation Conditions: A racemic mixture of ibuprofen was employed using an injection

volume of 10 μL, a chromatogram run time of 10 min, and the following mobile phases

and flow rates: a 90:10 hexanes/isopropanol mixture was used with a flow rate of 1.0 mL

89

min-1 for baseline separation (i.e., 1% overlap with a racemic mixture); a 82.5:17.5

hexanes/isopropanol mixture and a flow rate of 0.8 mL min-1 were used for slightly poorer

resolution studies (i.e., 4% overlap); finally, a 72.5:27.5 hexanes/isopropanol and a flow

rate of 0.8 mL min-1 were used for the worst resolution employed (i.e., 17% overlap). In

each instance 0.4% v/v NH4OAc was present in the isopropanol and the separations were

monitored at 220, 225, 230, 235, 240, 254, and 262 nm.

Integration Parameters: For a listing of each parameter and its value or the method used,

see the appendix. Slope sensitivities vary with the monitoring wavelength and the result

at 254 nm was taken from a range of values where the ees for both (R)- and (S)-ibuprofen

remained constant. This parameter was then scaled for the other wavelengths using the

UV spectrum of 3.1 as given by eq. 3.1 and values of 0.10, 4.5, 4.1, 2.3, 0.84, 0.20, and

0.14 were employed for 254, 220, 225, 230, 235, 240, and 262 nm, respectively; the

corresponding Ax/A254 ratios are 1.0, 45, 41, 23, 8.4, 2.0, and 1.4.

sx = Ax/A254 • s254 (3.1)

Polarimetry: Optical rotations were taken with an automatic polarimeter with a 0.5 dm

cell. Solutions with a concentration of 2 g/100 mL were made by dissolving 100 mg of

each enantiomer in absolute ethanol in 5 mL volumetric flasks. Ten measurements at the

indicated temperature were taken and the averaged values along with their standard

deviations as follows, (S)-3.1: [ɑ]D20 +58.40 ± 0.10° and (R)-3.1: [ɑ]D20 -58.15 ± 0.28°.

These results were compared to the literature value for (S)-ibuprofen ([ɑ]D20 +59° (c 2.0,

ethanol))32 to obtain the ees of the commercial samples of 3.1 (i.e., 99.0 ± 0.2% (S) and

98.6 ± 0.5% (R)). A least squares fitting of the enantiopurities of (S)- and (R)-3.1 using the

HPLC data in Tables 3.1 and 3.3 were in good accord with our rotation determinations

(see the appendix).

90

Chapter 4: Expanding the Reaction Scope of a Chiral Charge-Enhanced

Thiourea and Improving its Reactivity and Selectivity With a Brønsted Acid

Cocatalyst

4.1 Introduction

Small, metal-free molecules have been employed as catalysts in a variety of chemical

transformations.1 Brønsted acid organocatalysts commonly facilitate reactions through

hydrogen bonds that lower activation barriers and provide organization within transition

states.2 Many different structural motifs of these rate-enhancing compounds have been

reported,3,4 and thioureas are the most extensively studied class of double hydrogen bond

donors.5,6 Due to their simple construction, many achiral and chiral thiourea and urea

derivatives have been synthesized and successfully employed as organocatalysts.

Catalyst loadings are typically 10-20 mol%7 and therefore, the development of more

reactive catalysts is a focal point in this field.8

For ureas and thioureas, self-aggregation is one pitfall that can account for their limited

reactivities.9,10 To address this issue, synthetic chemists have employed internal and

external strategies to disrupt these interactions (Figure 4.1), thereby maximizing the

amount of free catalyst in solution. Intramolecular interactions that bind the oxygen or

sulfur atom of the active functional group with a protonated pyridinium ring,11 boron12–15

and palladium16 Lewis acids, and a larger network of hydrogen bonds17,18 have been

investigated (Figure 4.1a). In contrast, the addition of a Brønsted19,20 or Lewis21 acid

cocatalyst has also been shown to significantly impact the reactivities and selectivities of

these hydrogen bonding catalysts (Figure 4.1b).

91

Figure 4.1. Internal (a) and external (b) strategies to prevent thio(urea) aggregation.

The acidities of Brønsted acids with the same binding motifs generally correlate with

their reactivities and selectivities.22 Consequently, electron-withdrawing substituents are

utilized to improve reactivity, where the bis(3,5-trifluoromethyl)phenyl group has emerged

as a privileged framework in this research area.23,24 This aromatic scaffold is commonly

embedded in the structure of thio(ureas), and Schreiner’s thiourea (4.1, Figure 4.2) is

regarded as a gold standard of reactivity.25 Not only do the four CF3 groups increase the

acidity of the N-H bonds in the active site of the catalyst, but their presence also polarizes

the aryl C-H bonds which can engage in an intramolecular hydrogen bond with the sulfur

atom (Figure 4.2). This interaction provides rigidity in the catalyst, stabilizes the more

reactive (Z,Z) conformer, and helps prevent self-association with other thiourea

molecules.25,26

92

Figure 4.2. Schreiner’s thiourea and its hydrogen bonding interactions.

More recently, Yang Fan of the Kass group has shown that charged substituents have

a significant impact on the reactivities of achiral thioureas.27 In this study, one N-

methylpyridinium substituent was found to be more effective than four CF3 groups (i.e.,

Schreiner’s thiourea 4.1) in a variety of chemical transformations.26 Following this initial

report, a N-methylpyridinium thiourea bearing the cis-1-amino-2-indanol moiety (4.2) was

explored as a catalyst in an asymmetric Friedel-Crafts reaction between indole (4.3,

Scheme 4.1) and trans-β-nitrostyrene (4.4).28 Excellent yields could be achieved and

moderate to good selectivities were obtained at reduced temperatures (-35 °C), but a 10

mol% catalyst loading and long reaction times (2-3 d) were required to afford these results.

In this chapter, the impact of various Brønsted acid cocatalysts on the reactivity and

selectivity of thiourea 4.2 are presented. New chemical transformations catalyzed by the

charged compound were also explored and its reactivity and selectivity were compared

against its neutral analogue 4.5 and Schreiner’s thiourea 4.1.

93

Scheme 4.1. An asymmetric Friedel-Crafts reaction catalyzed by charged chiral thiourea

4.2.

Figure 4.3. Thiourea catalysts screened in this work.


The effect of additives on the reactivity and selectivity of the mono-charged thiourea

4.2 was first discovered when attempting to replicate the results reported by Yang Fan in

an asymmetric Friedel-Crafts reaction between indole and trans-β-nitrostyrene in

chloroform (Table 4.1).28 Entries 1 and 2 give the results that were collected by Fan.28 At

room temperature, complete conversion and a 75:25 er were obtained in 2 d. The reaction

was slower when cooled to -35 °C (76% conversion in 2 d) but a more enantiopure product

was obtained (91:9 er). When the same conditions were employed to replicate those

results, poorer reactivities and enantioselectivities were observed.

94

Table 4.1. Attempts to Replicate the Results Obtained by Fan.a

That is, a 93% conversion and 62.9:37.1 ± 0.029 er was obtained at room temperature

(entry 3), a 12% loss in enantioselectivity compared to entry 1. Similarly, less product (54%

conversion versus 76%) of lower enantiopurity (78.6:21.4 ± 0.3 er versus 91:9) was

collected at -35 °C (entries 4 and 2, respectively). The only significant difference between

the experiments of entries 1-2 and 3-4 was the purification of the reaction solvent.

Chloroform is commonly contaminated with HCl and therefore, it was treated with base

(K2CO3) and passed through a column of activated alumina prior to use in entries 3 and

4. Fan’s solvent, however, was used as received. Thus, the presence of a Brønsted acid

cocatalyst was hypothesized to account for the discrepancies in these results since p-

TsOH was shown not to catalyze this transformation in a previous report.27 To address

this, the reaction was performed at -35 °C using chloroform directly from the supplier (i.e.,

no purification). A similar conversion (54-55%) as before was observed (entries 4 and 5 in

Table 4.1), but a 5% increase in enantioselectivity was obtained (78.6:21.4 ± 0.3 er versus

83.3:16.7 ± 0.0). Taken together, the preliminary results in Table 4.1 suggest that HCl

might act as a cocatalyst and enhance the utility of charged thiourea 4.2. This possibility

entry temp (°C) conv. (%)b erc

1d rt 100 75:25 2d -35 76 91:9 3e rt 93 62.9:37.1 ± 0.0 4e -35 54 78.6:21.4 ± 0.3 5f -35 55 83.3:16.7 ± 0.0

a[4.3] = 250 mM. [4.4] = 83 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained with HPLC on a chiral column. dData from ref 28. eThe solvent was treated with K2CO3

and a column of activated alumina. fThe solvent was used without any purification.

95

is precedented in that Brønsted acids, particularly mandelic acid, have been reported to

activate non-charged thioureas.19,20 It should also be noted that the amount of H2O present

is different in our experiments, and this also could account for the variation in the results.

To explore this matter further, a variety of Brønsted acid additives were investigated

and the results are given in Table 4.2. For ease of comparison, entries 1 and 2 are the

results obtained by Fan at room temperature and -35 °C, respectively.28

Table 4.2. Effect of Acid Additives in CDCl3.a

Base-washed and dried chloroform was used in all of the other cases to remove

adventitious acid impurities. Concentrated HCl was first screened as a cocatalyst at -35

°C. Using 10 and 20 mol% loadings (entries 3 and 4), similar conversions (60 and 56%)

and selectivities (about 82:18 and 84:16 er) were obtained, but these data were still inferior

to that collected by Fan (76% conversion and 91:9 er, entry 2). In entry 5, 20 mol% of HCl

entry additive (mol%) temp (°C) conv. (%)b erc

1d - rt 100 75:25 2d - -35 76 91:9 3e HCl (10) -35 60 81.7:18.3 ± 0.1 4e HCl (20) -35 56 83.7:16.3 ± 0.1 5e HCl (20) rt 100 72.0:28.0 ± 0.0 6e,f - -35 45 72.9:27.1 ± 0.0 7e TFA (10) -35 0 - 8e AcOH (10) -35 45 74.6:25.4 ± 0.0 9e (±)-mandelic acid (10) -35 64 82.8:17.2 ± 0.0

a[4.3] = 250 mM. [4.4] = 83 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained with HPLC on a chiral column. dData from ref 28. eThe solvent was treated with K2CO3

and a column of activated alumina. fThiourea catalyst was washed with HCl prior to use.

96

was employed at room temperature affording quantitative conversion and 72:28 er, nearly

identical to those reported by Fan (100% conversion, 75:25 er, entry 1).

Based on entries 3-5, it was hypothesized that under our reaction conditions the HCl

cocatalyst is less soluble at -35 °C than at room temperature, and this would account for

the poorer results in the former case. To circumvent this concern, the thiourea-HCl adduct

was premade by washing the thiourea with an HCl solution and then concentrating it with

a rotary evaporator. The resulting material was employed in the reaction (entry 6) but a

smaller conversion (45% vs 56 or 60%) and lower selectivity (73:27 er vs 82:18 or 84:16

er) was observed than when the thiourea and HCl were individually added (entries 3 and

4). Thus, the use of HCl is sensitive to the reaction conditions presumably due to solubility

issues and/or the presence of varying amounts of water.

To try and readily overcome the difficulties using concentrated HCl, carboxylic acids

were explored at -35 °C. When trifluoroacetic acid (TFA) was used (entry 7), a precipitate

immediately formed upon its addition and no product was observed. Presumably an

insoluble salt of the thiourea formed, leading to the loss of the catalyst. Use of a weaker

acid (acetic acid, entry 8), afforded a 45% conversion and an er of 74.6:25.4. Lastly,

racemic mandelic acid was employed (entry 9) since this cocatalyst has already been

shown to be effective in this transformation with neutral thiourea 4.5.19,20 A conversion of

64% and selectivity of 82.8:17.2 was observed, similar to the results obtained with HCl

(entries 3 and 4). Given the results in Table 4.2, HCl and (±)-mandelic acid were found to

give the best results.

The investigation of the effect of Brønsted acids as cocatalysts was continued by

changing the solvent to d2-dichloromethane (Table 4.3). Residual acid impurities are less

prevalent in this solvent and the increased dielectric constant compared to chloroform was

97

hypothesized to help solvate any acid bound adducts. Results that were reported by Fan

are given in entry 1,28 where an 81% conversion and 74:26 er was observed after 44 h at

room temperature.

Table 4.3. Effect of Acid Additives in CD2Cl2.a

When no cocatalyst was employed, less product (66% conversion) and a lower

enantiopurity (62.2:37.8 er) was obtained under the same conditions except for drying the

solvent. The effect of an acid cocatalyst was immediately recognized when 10 mol% of

HCl was used (entry 3). The conversion (86%) and selectivity (76:24) were slightly

improved compared to the results report by Fan in entry 1. Increasing the amount of HCl

entry additive (mol%) conv. (%)b erc

1d - 81 74:26 2 - 66e 62.2:37.8 ± 0.0 3 HCl (10) 86 76.0:24.0 ± 0.0 4 HCl (20) 86 79.6:20.4 ± 0.0 5 HCl (30) 81 78.6:21.4 ± 0.0 6 HCl (40) 82 80.1:19.9 ± 0.0 7f HCl (10) 1 - 8 (±)-mandelic acid (10) 85 79.9:20.1 ± 0.0 9f (±)-mandelic acid (10) 2 - 10 HPF6 (10) 82 73.0:27.0 ± 0.1 11 HPF6 (20) 85 79.4:20.6 ± 0.0 12f HPF6 (10) 2 - 13 HBF4 (10) 73 66.1:33.9 ± 0.0 14 HBF4 (20) 72 67.2:32.8 ± 0.0 15f HBF4 (10) 0 - 16 H2O (5560)g 61 71.1:28.9 ± 0.1 17 HCl (10) + NaBAr

F4 (10) 90 74.3:25.7 ± 0.0

18 HCl (20) + NaBArF

4 (10) 90 73.3:26.7 ± 0.0 19 HCl (20) + NaBAr

F4 (20) 91 71.9:28.1 ± 0.0

a[4.3] = 250 mM. [4.4] = 83 mM in dried CD2Cl2. bCalculated from a 1H NMR spectrum of the

reaction mixture. cObtained with HPLC on a chiral column. dData from ref 28. eCollected after 48 h. fNo thiourea catalyst was used. g50 µL was added.

98

cocatalyst to 20 mol% (entry 4) afforded similar reactivity to 10 mol%, but an increase of

almost 4% in er (79.6:20.4) was observed. Compared to chloroform (entry 5 in Table 4.2),

dichloromethane was found to afford a more selective transformation at room temperature.

In entries 5 and 6, 30 and 40 mol% of HCl was employed and a slight decrease in reactivity

(81-82% conversion) was observed, but the enantiopurity of the product was largely

unchanged. A control experiment where no thiourea catalyst was used indicated that the

HCl cocatalyst is ineffective by itself (entry 7), which is in accord with Fan’s observation

that 1 mol% of p-TsOH does not lead to product formation.27 Racemic mandelic acid was

also employed as a cocatalyst (10 mol%, entry 8), and similar results (85% conversion

and 79.9:20.1 er) were obtained compared to 20 mol% of HCl (entry 4). Additionally,

mandelic acid was found not to catalyze this transformation by itself (entry 9).

The counteranion of these charged catalysts has been shown to affect their reactivities

and selectivities.30,31 That is, catalytic activity is diminished when the anion can hydrogen

bond with the active site of the catalyst. Thus, weakly coordinating anions such as

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BArF4) are used in order to minimize cation-

anion interactions. In an analogous fashion, it was hypothesized that chloride may be

hindering the thiourea catalyst and improved results could be achieved if a less

coordinating anion was employed. To test this hypothesis, HPF6 and HBF4 were examined

as cocatalysts. Reactions that involved HPF6 (entries 10-12) afforded very similar results

to when HCl was used, reaching 85% conversion and 79.4:20.6 er when 20 mol% of

cocatalyst was employed. However, HBF4 (entries 13-15) afforded poorer reactivities and

selectivities compared to HPF6 and HCl (72-73% conversion and 66.1:33.9-67.2:32.8 er).

Since these acids are water based, a control experiment where H2O (≈50 µL) was used

as an additive is given in entry 16. This resulted in slightly diminished reactivity (61%

99

conversion) but improved selectivity (71.1:28.9 er) compared to when no cocatalyst (entry

2) or HBF4 (entries 13-14) was employed.

Lastly, HBArF4 was explored. This acid is unstable by itself and therefore, is commonly

used as a dietherate adduct (Brookhart’s acid).32 Since the ether may inhibit the thiourea

catalyst, this cocatalyst was generated in situ by adding HCl and NaBArF4 together in

dichloromethane containing catalyst 4.2. Precipitation of NaCl would generate HBArF4

which could immediately complex with the thiourea. Gratifyingly, increased conversions

were observed (≥90%, entries 17-19). Selectivities, however, were diminished compared

to the reactions with HCl, HPF6, and (±)-mandelic acid, which all afforded similar results.

This lower ee may be due to the presence of the sodium cation but was not pursued

further.33

Since more selective transformations were obtained in dichloromethane than in

chloroform at room temperature, a temperature screen was carried out with the former

solvent (Table 4.4). Entries 1-3 show the temperature dependence when HCl was

employed as the cocatalyst.

Table 4.4. Temperature Effects in CD2Cl2.a

entry additive (mol%) temp (°C) conv. (%)b erc

1 HCl (20) rt 86 79.9:20.1 ± 0.0 2 HCl (20) 0 59 77.6:22.4 ± 0.0 3 HCl (20) -35 14 62.4:37.6 ± 0.0 4 (±)-mandelic acid (10) rt 85 79.9:20.1 ± 0.0 5 (±)-mandelic acid (10) 0 73 78.0:22.0 ± 0.0 6 (±)-mandelic acid (10) -35 18 68.0:32.0 ± 0.0

a[4.3] = 250 mM. [4.4] = 83 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained with HPLC on a chiral column.

100

Lowering the temperature from room temperature to 0 and -35 °C led to poorer

conversions over the same time period (i.e., 86% to 59 and 14%, respectively).

Additionally, the observed enantioselectivities of the product were reduced when colder

conditions were used (79.9:20.1 er to 77.6:22.4 and 62.4:37.6, respectively). When (±)-

mandelic acid was employed (entries 4-6), a similar trend was observed where both

reactivity and selectivity diminished as the temperature was lowered. A possible

explanation for these results is that the solubility of the thiourea-cocatalyst adduct

decreases as the temperature decreases, leading to less efficient and selective

transformations. Association constants between the various species also vary with

temperature and therefore, also could be responsible for slower and lower ee

reactions.Overall these results in Tables 4.1-4.4 show that the introduction of a Brønsted

acid cocatalyst can improve the reactivities and selectivities of charge-enhanced thiourea

catalysts just as reported by Herrera for a non-charged analog.19,20 This strategy can be

exploited going forward when investigating a variety of chemical transformations.

After investigating the Friedel-Crafts alkylation, additional transformations were

studied with mono-charged thiourea 4.2 and a cocatalyst. First, an oxa-Pictet-Spengler

reaction between tryptophol (4.6, Scheme 4.2) and benzaldehyde (4.7) was targeted since

this transformation has been shown to be facilitated by a variety of thiourea catalysts along

with a protonated indoline ester cocatalyst (4.8).34

Scheme 4.2. An oxa-Pictet-Spengler reaction catalyzed by thioureas and a protonated

indoline cocatalyst.

101

In Table 4.5, a screen of thiourea catalysts without any cocatalyst was examined.

Schreiner’s thiourea 4.1 (entry 1) was capable of catalyzing this reaction, affording a 64%

conversion of racemic product in 92 h. Exchange of one of the bis(3,5-

trifluoromethyl)phenyl substituents for the chiral cis-1-amino-2-indanol moiety ((1S,2R)-

4.5, entry 2) diminished the catalytic reactivity and no product was observed under the

same conditions. The mono-charged thiourea (1S,2R)-4.2 (entry 3) exhibited the best

activity, reaching 85% conversion after 92 h. The selectivity in the product, however, was

essentially racemic (49.2:50.8 er).

Table 4.5. Screen of Thiourea Catalysts for an Oxa-Pictet-Spengler Reaction.a

Given these results, acid cocatalysts were explored (Table 4.6). In entry 1, 20 mol%

of HCl was employed with the charged thiourea (1S,2R)-4.2, which resulted in an

improved reactivity. That is, a 91% conversion was obtained in 40 h versus 85%

conversion in 92 h without any cocatalyst (Table 4.5, entry 3). The enantioselectivity,

however, was largely unchanged as racemic product was obtained. The use of a chiral,

entry catalyst conv. (%)b erc

1 4.1 64 rac 2 (1S,2R)-4.5 trace - 3 (1S,2R)-4.2 85 49.2:50.8 ± 0.1

a[4.6] = 50 mM. [4.7] = 605 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained with HPLC on a chiral column.

102

protonated indoline ester cocatalyst 4.8 with the mono-charged thiourea (1S,2R)-4.2 is

given in entry 2. Impressive reactivity was observed, reaching 98% conversion in 30 min

and a slight preference for one enantiomer was recorded (48.9:51.1 er). Reactions

performed in toluene were most selective in a previous report,34 but the charged thiourea

4.2 has poor solubility in this solvent. Thus, a 1:1 solvent mixture of toluene and

dichloromethane was explored in entry 3. A slight decrease in conversion was observed

(92% in 0.7 h) and interestingly the major enantiomer was reversed under these

conditions, albeit still in nearly a racemic amount (52.0:48.0 er).

Table 4.6. Screen of Cocatalysts for an Oxa-Pictet-Spengler Reaction.a

entry catalyst additive (mol%) time (h) conv. (%)b erc

1 (1S,2R)-4.2 HCl (20) 40 91 49.7:50.3 ± 0.0 2 (1S,2R)-4.2 4.8 (10) 0.5 98 48.9:51.1 ± 0.0 3d (1S,2R)-4.2 4.8 (10) 0.7 92 52.0:48.0 ± 0.1 4 4.1 4.8 (10) 0.6 93 50.3:49.7 ± 0.1 5 (1S,2R)-4.5 4.8 (10) 1.0 92 50.6:49.4 ± 0.0 6 - 4.8 (10) 1.3 98 53.5:46.5 ± 0.0 7 (1R,2S)-4.2 4.8 (10) 0.5 100 50.2:49.8 ± 0.0 8 (1R,2S)-4.5 4.8 (10) 1.0 90 50.0:50.0 ± 0.0

a[4.6] = 50 mM. [4.7] = 605 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained with HPLC on a chiral column. dSolvent was 1:1 toluene/DCM.

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Use of Schreiner’s thiourea 4.1 and the indoline cocatalyst 4.8 (entry 4) exhibited 93%

conversion to the racemic product in 0.6 h, slightly less than when the charged thiourea

was employed (entry 2). The chiral, neutral thiourea (1S,2R)-4.5 exhibited the least

reactivity of the thioureas (92% conversion in 1 h) under these conditions, consistent with

the data in Table 4.5. When no thiourea was used (entry 6), the protonated indoline 4.8

was shown to promote this reaction as efficiently as when the neutral thiourea 4.5 was

also employed (entry 5). Interestingly, a different selectivity of 53.5:46.5 er was obtained

when no thiourea catalyst was present. Since the preferred enantiomer formed by additive

4.8 is opposite from the product formed with thiourea (1S,2R)-4.2 (entry 2), it was

hypothesized that a mismatched case between the cocatalysts may be suppressing the

stereoselectivity. Consequently, the enantiomers of the charged ((1R,2S)-4.2) and neutral

((1R,2S)-4.5) thioureas were synthesized and examined (entries 7 and 8, respectively).

Similar reactivities and poorer selectivities were observed in both cases (compare entries

2 and 7, and 5 and 8).

Given that these transformations proceeded quickly, a lower temperature was used to

slow the reaction rates (Table 4.7), and hopefully improve the observed

enantioselectivities in the product. In entry 1, the background reaction catalyzed by the

indoline cocatalyst was negligible at -30 °C after 1 h. Use of the enantiomers of the mono-

charged thiourea catalyst (entries 2 and 3) afforded slightly differing results. Thiourea

(1S,2R)-4.2 afforded a 15% conversion and a 53.8:46.2 er after 1 h, whereas the

enantiomer (1R,2S)-4.2 gave a 21% conversion and a 59.2:40.8 er. These results suggest

that the reaction proceeds too quickly at room temperature to distinguish between

matched and mismatched cases. At lower temperatures (such as -30 °C), however, the

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two enantiomers of 4.2 can be differentiated. The observed improvement in reactivity and

selectivity is encouraging, but more optimization is required.

Table 4.7. Temperature Screen for an Oxa-Pictet-Spengler Reaction.a

Another Brønsted acid catalyzed transformation that was examined was a Michael

addition between β-keto ester 4.9 and methyl vinyl ketone (4.10, Table 4.8). This reaction

has been reported to be catalyzed by neutral, BINOL-based phosphoric acids.35 Since

thioureas are less acidic than phosphoric acids, the charge-enhanced thiourea 4.2

coupled with a cocatalyst ((±)-mandelic acid) was envisioned to promote this process.

Following the reported reagent concentrations,35 a 4% conversion to the product was

observed at 40 °C in dichloromethane after 1 d. Switching the solvent to toluene (the

preferred solvent in the previous study)35 led to a 9% conversion in the same amount of

time. Currently, the chiral HPLC method to separate the enantiomers of the product has

not been developed so the selectivity from these trials has yet to be determined. Future

work entails optimizing the reaction conditions such as the reaction temperature and

concentrations of the substrates.

entry catalyst conv. (%)b erc

1 - 0 - 2 (1S,2R)-4.2 15 53.8:46.2d

3 (1R,2S)-4.2 21 59.2:40.8d

a[4.6] = 50 mM. [4.7] = 605 mM. [4.8] = 5.0 mM. bCalculated from a 1H NMR spectrum of the reaction

mixture. cObtained with HPLC on a chiral column. dOnly one measurement was made.

105

Table 4.8. Preliminary Results for a Michael Addition Reaction Catalyzed by a

Charged Thiourea.a

The last transformation that was attempted with the mono-charged thiourea catalysts

was an asymmetric Friedel-Crafts alkylation between indole (4.3) and 2,2,2-

trifluoroacetophenone (4.11, Scheme 4.3), which has been catalyzed by a doubly charged

phosphoric acid developed in the Kass laboratory.36 Since thioureas are inherently less

acidic that phosphoric acids, and one charged center is less activating than two, it was

hypothesized the mono-charged thiourea 4.2 would react slowly, so (±)-mandelic acid was

added as a cocatalyst in the initial efforts. Under similar reaction conditions that have been

reported,36 no product was observed after 1 d. Further work on this reaction requires

optimizing the reaction conditions, but it should be recognized that the mono-charged

thiourea 4.2 may not be a strong enough catalyst to promote this transformation.

Scheme 4.3. Attempted asymmetric Friedel-Crafts alkylation.

entry solvent temp (°C) time conv. (%)b

1 CH2Cl2 40 23 h 4 2 toluene 40 23 h 9

a[4.9] = 200 mM. [4.10] = 600 mM. bCalculated from a 1H NMR spectrum of the crude mixture.

106

4.3 Conclusions and Future Work

In summary, this chapter describes efforts to improve the reactivity and selectivity of a

mono-charged thiourea catalyst (4.2) that has been developed in our laboratory. Addition

of a Brønsted acid cocatalyst has been shown to improve its catalytic reactivity and

enantioselectivity in a Friedel-Crafts reaction.

The reaction scope of thiourea 4.2 also has been investigated. An oxa-Pictet-Spengler

reaction was shown to proceed with this compound, but poor selectivity has been

observed to date. Initial studies have shown promise in a Michael addition, and more work

is required for this system.

The diversity of substrates that can interact with this catalyst should continue to be

investigated. A review highlighting the cis-1-amino-2-indanol moiety has provided other

chemical processes that have been catalyzed by analogous thioureas like 4.5.37 For

example, other Michael acceptors such as α,β-unsaturated acyl phosphonates38 and β,γ-

unsaturated α-ketoesters39 have been reacted with indoles in the presence of thiourea 4.5.

An asymmetric 1,4-addition of N,N-dialkylhydrazones (4.12) to β,γ-unsaturated α-

ketoesters (4.13) would be an interesting reaction to investigate (Scheme 4.4).40

Scheme 4.4. An asymmetric 1,4-addition of N,N-dialkylhydrazones to β,γ-unsaturated α-

ketoesters catalyzed by thiourea 4.5.

107

4.4 Experimental

General. All stir bars, needles, and glassware (vials, NMR tubes, and round-bottomed

flasks) were dried at 120 °C for at least 16 h, and glass syringes were stored in a vacuum

desiccator over Drierite (with colored indicator) for at least 16 h. Molecular sieves and

alumina (neutral, Brockman I, standard grade, 150 mesh, 58 Å) were activated at 300 °C

for at least 24 h. Copper (II) sulfate was obtained from Mallinckrodt and dried at 300 °C

for 24 h.

Bruker Avance III HD 400 or 500 MHz instruments collected all 1H NMR spectra and

were referenced using residual solvent signals in CD2Cl2 (δ 5.32) and CDCl3 (δ 7.26).

Purification by MPLC was performed on RediSep Rf gold® 4-gram silica gel columns with

a CombiFlash® Rf automated flash chromatography system from Teledyne Isco. Inc.

Cambridge Isotope Laboratories supplied the deuterated solvents, where d2-

dichloromethane was dried with 3 Å molecular sieves for at least 24 h prior to use.

Deuterated chloroform (CDCl3) was treated with potassium carbonate and passed through

a column of activated alumina to remove any acid contaminants prior to storage over 3 Å

molecular sieves. Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (NaBArF4) was

obtained from AK Scientific as a 2.5 hydrate and the water was removed by activated

alumina and heating under reduced pressure as previously described.41,42 Trifluoroacetic

acid and acetic acid were dried over MgSO4, filtered, and stored over activated CuSO4

under inert atmosphere. L-(-)-Indoline-2-carboxylic acid and 3,5-bis(trifluoromethyl)phenyl

isothiocyanate were used as received from Oakwood Chemical and Alfa Aesar,

respectively. All other reagents were obtained from Sigma-Aldrich and also used without

further purification.

108

The mono-charged, chiral thiourea 4.2 and its enantiomer were prepared following a

previously reported procedure from our laboratory.28 Likewise, 1-(3,5-

bis(trifluoromethyl)phenyl)-3-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thiourea 4.5

and its enantiomer were synthesized using a literature procedure.19 The L-(-)-indoline-2-

carboxylic acid methyl ester HCl adduct 4.8 was obtained in two steps from L-(-)-indoline-

2-carboxylic acid as previously described.34,43 β-Ketoester 4.9 was synthesized from 1-

indanone following a reported procedure.44

Stock solutions (100 mM) of HCl, HPF6, and HBF4 were made to achieve the desired

catalyst loading. With this concentration, 50 µL of these solutions were equal to 1

equivalent (5 µmol) of the thiourea catalyst. To prepare these stock solutions, the volumes

of the concentrated acids shown below were added into a 2 mL volumetric flask and then

diluted to the line in the glass with the desired reaction solvent.

HCl – 17 µL of concentrated HCl (12 M)

HPF6 – 32 µL of concentrated HPF6 (6.2 M)

HBF4 – 26 µL of concentrated HBF4 (7.7 M)

General procedure for the Friedel-Crafts reaction between indole and trans-β-

nitrostyrene.

In a 6-dram vial under inert atmosphere, 5.0 µmol of catalyst and the chosen amount

of external Brønsted acid were added and dissolved in 300 µL of the reaction solvent. A

separate 2-dram vial was charged with 0.150 mmol of indole 4.3 and 0.050 mmol of trans-

β-nitrostyrene 4.4 under inert atmosphere and 300 µL of solvent was added. Both vessels

were cooled to the desired temperature before the entire indole solution was transferred

to the vial containing the catalyst via syringe over 10 s. The contents were then shaken

and allowed to react for 48 h. An aliquot of the reaction mixture at various times was diluted

109

with CDCl3 and a 1H NMR spectrum was obtained to calculate the percent conversion to

the desired product. The remaining material was subjected to MPLC on silica gel (100%

hexanes for 1 min followed by an 8 min linear gradient to 100% CH2Cl2) to isolate the

product for chiral HPLC analysis with a RegisCell column (75:25 hexanes / isopropanol,

1.0 mL min-1, τmajor = 17.2 min, τminor = 20.7 min [Rs = 3.2], λ = 280, 220, and 230 nm).29

General procedure for the oxa-Pictet-Spengler reaction between tryptophol and

benzaldehyde.

In a 6-dram vial under inert atmosphere, 0.030 mmol (4.8 mg) of tryptophol 4.6, 0.003

mmol of the desired catalyst and cocatalyst were dissolved in 560 µL of the reaction

solvent and the vial was cooled to the desired reaction temperature. Then 0.363 mmol

(37.0 µL, 38.5 mg) of benzaldehyde 4.7 was added by syringe in 1-2 s, the vial was shaken

for 5 s, and then the contents were transferred into an NMR tube and sealed with a cap

and electrical tape. Once the reaction was completed, the mixture was subjected to MPLC

on silica gel (100% hexanes for 2 min followed by a 3 min linear gradient to 10% ethyl

acetate which was held for 7 min) to isolate the product for chiral HPLC analysis with a

RegisPack column (95:5 hexanes / isopropanol, 1.25 mL min-1, τ1 = 10.3 min, τ2 = 12.4

min [Rs = 4.3], λ = 280, 254, and 220 nm).29

General procedure for the Michael reaction between β-ketoester 4.9 and methyl

vinyl ketone.

In a sealed 2-dram vial, 0.20 mmol of the β-ketoester 4.9 and 0.02 mmol of the catalyst

and cocatalyst were dissolved in 1 mL of solvent, and the vial was heated to 40 °C. Methyl

vinyl ketone 4.10 (49 µL, 0.60 mmol) was then added in one portion and the vial was

110

shaken for 5 s. An aliquot of the reaction mixture was taken at various times and diluted

with CD2Cl2 to determine the extent of the reaction.

Attempted Friedel-Crafts reaction between indole and 2,2,2-trifluoroacetophenone.

In a 2-dram vial, 0.007 mmol of the catalyst and cocatalyst and 0.140 mmol (16.4 mg)

of indole 4.3 were dissolved in 250 µL of CD2Cl2. 2,2,2-Trifluoroacetophenone 4.11 (23.6

µL, 29.3 mg, 0.168 mmol) was added in one portion and the vial was shaken for 5 s. The

entire contents were then transferred into an NMR tube that was capped and sealed with

electrical tape.

111

Chapter 5: Investigation of a Computationally Designed Thiourea for

Improved Catalytic Performance

5.1 Introduction

The cis-1-amino-2-indanol framework is a commercially available, chiral motif that is

commonly used in thiourea and urea catalysis (Figure 5.1).1 This scaffold provides rigidity

in the catalyst’s structure and the pendant hydroxyl group can act as a hydrogen bond

donor or acceptor that can lead to different interactions with a variety of substrates. Former

Kass group member Dr. Yang Fan employed this asymmetric strategy with a charge-

enhanced thiourea (5.1) and studied its reactivity and selectivity in a Friedel-Crafts

reaction between substituted indole derivatives and a variety of trans-β-nitrostyrenes

(Scheme 5.1).2

Figure 5.1. A thiourea bearing the cis-1-amino-2-indanol framework.

Scheme 5.1. An asymmetric Friedel-Crafts alkylation catalyzed by charged thiourea 5.1.

112

Excellent yields could be achieved with this catalyst, but only moderate to good

selectivities (78-90% ee) could only be obtained at reduced temperatures (-35 °C) and

prolonged reaction times.2 In order to improve the selectivity of this mono-charged

thiourea, computational models of the diastereomeric transition states leading to the two

product enantiomers were examined. Since a counteranion complicates these

calculations and its absence would afford unreliable results (i.e., the charge-enhanced

effect from the N-alkylated pyridinium would be overestimated), the charged catalyst 5.1

was modeled with its neutral analogue bearing a bis(trifluoromethyl)phenyl ring (5.2).

Three substituted cis-1-amino-2-indanol variants (R = H, CN, and t-Bu) were surveyed by

Dr. Alireza Shokri and Dr. Steven Kass using M06-2X/6-311G(d,p) and a PCM solvation

model for dichloromethane (see appendix for geometries and energies). In all cases, the

alcohol group of the chiral moiety was found to act as hydrogen bond donor to the

nitrostyrene and a hydrogen bond acceptor with the N-H bond of the indole (Figure 5.2).3

The corresponding free energies of activation leading to each product enantiomer are

given in Table 5.1.

Figure 5.2. The general mode of activation of thioureas 5.2 where R = H, CN, or t-Bu.

113

Table 5.1. Calculated Free Energies of Activation Leading to Each Product

Enantiomer Catalyzed by Substituted cis-1-Amino-2-indanol Thioureas.a

The presence of an electron withdrawing group (R = CN) led to higher energy

transitions states (ΔGǂ = 17.4 and 20.0 kcal mol-1) than the parent compound (R = H, ΔGǂ

= 15.9 and 18.0 kcal mol-1). These results indicate slower, but more selective reactions

(ΔΔGǂ = 2.6 and 2.1 kcal mol-1 when R = CN and H, respectively) would take place if the

cyano-substituted amino indanol was employed. When the sterically encumbered

analogue (R = t-Bu) was examined, it was predicted to lead to the fastest (ΔGǂ (S) = 15.3

kcal mol-1) and most selective (ΔΔGǂ = 2.8 kcal mol-1) transformations of the three thiourea

derivatives that were modeled. Given these results, the mono-charged thiourea 5.3

containing this bulkier framework was hypothesized to improve upon the results reported

by Fan.2 Consequently, the synthesis of this computationally designed catalyst and its 3,5-

bis(trifluoromethyl)phenyl analogue were explored.

The construction of the thiourea functional group with a pyridinium moiety had already

been developed by Dr. Yang Fan using a charged isothiocyanate 5.4 and a cis-1-amino-

2-indanol,2 so 2-tert-butyl-cis-1-amino-2-indanol (5.5) was a desired intermediate

(Scheme 5.2). This compound could be obtained through the hydrolysis of the

corresponding cis-oxazolidinone 5.6, which was envisioned to be achieved from an

intramolecular benzylic C-H amidation from carbamate 5.7. This intermediate can be

R ΔGǂ (S) ΔGǂ (R) ΔΔGǂ (R – S)

H 15.9 18.0 2.1

CN 17.4 20.0 2.6

t-Bu 15.3 18.1 2.8

aEnergies are given in kcal mol-1 at 298 K.

114

generated by reacting an isocyanate with 2-tert-butylindanol (5.8), which could be

obtained via the 1,2-additon of 2-indanone (5.9) with a Grignard or organolithium reagent.

With this retrosynthesis in hand, efforts to synthesize the target thiourea 5.3 were pursued

with the assistance of LANDO undergraduate Khoi Luu from Grinnell College.

Scheme 5.2. Retrosynthetic analysis of the target thiourea catalyst 5.3.


The 1,2-insertion of the tert-butyl group into 2-indanone (5.9) was found to be difficult

as t-BuMgCl did not generate the product and use of t-BuLi afforded a 15% conversion to

the desired tertiary alcohol in the presence of CeCl3 (Scheme 5.3).4 These results raised

questions whether the cerium reagent was properly prepared (i.e., anhydrous CeCl3 was

prepared from CeCl3·7H2O)5 or if the bulky alkyl chain hindered the nucleophilicity of the

organocerium complex.

Scheme 5.3. Reagents and corresponding conversions of 1,2-additions into ketone 5.9.

115

To address these concerns, i-PrMgCl was employed under the same conditions and

a significantly higher conversion (up to 89%) of the isopropyl tertiary alcohol was

observed. Thus, the CeCl3 was sufficiently dried and the size of the alkyl group of the

organometallic reagent impacted the efficiency of this reaction. Additionally, a slow rate of

addition of the ketone to the organocerium reagent was found to minimize a self-aldol side

reaction.4

While optimizing the 1,2-addition of ketone 5.9 with t-BuLi, the proposed synthetic

route was pioneered with the isopropyl variant 5.10, and the subsequent step converted

the alcohol into a carbamate moiety (Scheme 5.4). Since our laboratory already had p-

toluenesulfonyl isocyanate (5.11) in stock, the p-toluenesulfonyl carbamate 5.12 was

synthesized in moderate yield (68%).6 Additionally, carbamate 5.14 was obtained in

excellent yield using trichloroacetyl isocyanate (5.13) and a basic workup.7

Scheme 5.4. Synthesis of carbamate intermediates 5.12 and 5.14.

The following transformation was an intramolecular benzylic C-H amidation, and

similar processes have been accomplished with a variety of metal catalysts and under

metal-free conditions.8 Initial attempts involved exposing carbamate 5.12 to di-tert-butyl

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peroxide in the presence of a copper (I) catalyst (Scheme 5.5),8a,8b but incomplete

consumption of the starting material was observed based on the crude 1H NMR spectrum

of the reaction. At first, new 1H NMR signals were tentatively assigned to the desired

oxazolidinone 5.15. However, sulfamide 5.17 was identified in the crude mixture,

indicating the carbamate functional group had eliminated and alkene 5.16 was formed

under these conditions (note: compounds 5.15 and 5.16 have the same number of protons

and provide similar 1H NMR spectra). After purification, the identity of the major product

was determined to be alkene 5.16 by its IR spectrum, which did not contain any carbonyl

frequencies, and comparing its 1H NMR spectrum with a published report of 5.16.4a Use

of carbamate 5.14 did not change the outcome of this reaction, and similar results were

obtained under metal-free conditions using DDQ.8e One attempt employing an iron

catalyst8c to facilitate this transformation afforded a complex mixture of compounds that

was not investigated further.

Scheme 5.5. A copper-catalyzed benzylic amidation that resulted in alkene 5.16 and

sulfamide 5.17.

Subsequently, nitrene-based chemistry was explored with carbamate 5.14 and a

rhodium catalyst, following the conditions provided by Espino and Du Bois (Scheme 5.6).8d

This transformation led to high consumption of the starting material, afforded the desired

product 5.15, and alkene 5.16 was not detected. However, a competition of site selectivity

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was observed, where the tertiary C-H bond of the isopropyl moiety participated in C-H

activation with the rhodium catalyst and led to oxazolidinone 5.18; in general, a ratio of

2:1 of 5.15:5.18 was achieved. Despite the formation of the undesired isomer, the results

indicate these reaction conditions should afford an excellent yield when the tert-butyl

variant of 5.14 is employed (i.e., a tertiary C-H bond is not present in carbamate 5.7 so

the competing C-H activation cannot take place). If the isopropyl oxazolidinone 5.15 is

desired in the future, changing the ligands of the rhodium catalyst has been shown to

influence site selectivity.9

Scheme 5.6. A rhodium-catalyzed amidation and the observed distribution of products

5.15 and 5.18.

Next, the enantiomers of 5.15 were separated by HPLC using the chiral RegisPack

column (250 x 4.6 mm, 5 µm) from Regis Technologies with a 95:5 hexanes/isopropanol

mobile phase and a flow rate of 2.0 mL min-1. At this point, the 1,2-insertion of 2-indanone

(5.9) with t-BuLi (Scheme 5.1) was optimized, so semi-preparative HPLC on 5.15 was not

pursued. To complete the exploration of the synthetic route, a racemic sample of

oxazolidinone 5.15 was exposed to reported hydrolysis conditions to afford the 2-

isopropyl-1-amino-2-indanol 5.19 in 62% yield (Scheme 5.7).10 With this synthetic route

mapped out, the synthesis of the tert-butyl variant 5.5 was revisited.

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Scheme 5.7. The enantiomers of 5.15 and its hydrolysis to afford amino alcohol 5.19.

The 1,2-addition of t-BuLi to 2-indanone (5.9) was optimized to afford a 31%

conversion (on average) of 2-tert-butylindanol (5.8) with minimal byproducts (Scheme

5.8). Tertiary alcohol 5.8 was then reacted with trichloroacetyl isocyanate (5.13) followed

by a basic workup to obtain carbamate 5.7 in quantitative yield (31% yield over 2 steps

from 5.9). The rhodium-catalyzed, intramolecular, benzylic amidation afforded the racemic

oxazolidinone 5.6 in good yield (84%) and no competing C-H activation byproducts were

detected. Separation and collection of the enantiomers of 5.6 was carried out by semi-

preparative HPLC on a chiral column, resulting in samples of 99.0% ± 0.2% ee and 95.6%

± 0.2% ee.11,12 Each of the enantiomers was then hydrolyzed to afford the desired, chiral

cis-1,2-aminoalcohol 5.5 in 90% yield.

Scheme 5.8. Synthetic route of enantiopure 2-tert-butyl-cis-1-amino-2-indanol 5.5.

119

At this stage, the absolute stereochemistry of each of the enantiomers of 5.5 was

unknown. To address this issue, the less enantiopure sample (95.6% ± 0.2% ee) was

reacted with the charged isothiocyanate reagent 5.4 to afford the corresponding thiourea

5.202 and crystals of this iodide salt were grown via vapor diffusion with diethyl ether and

acetonitrile (Scheme 5.9).13 A X-ray crystal structure was then obtained and solved by

Brendan J. Graziano and Dr. Victor G. Young, Jr. at the University of Minnesota and the

absolute stereochemistry of the 2-tert-butyl-cis-1-amino-2-indanol was determined to be

1S,2S (see appendix for all X-ray data).

Scheme 5.9. Synthesis and absolute stereochemistry of thiourea salt (1S,2S)-5.20.

The final thiourea catalyst 5.3 was synthesized using the more enantiopure (99.0% ±

0.2% ee) (1R,2R)-2-tert-butyl-cis-1-amino-2-indanol (5.5, Scheme 5.10). After obtaining

the iodide salt 5.20 in high yield (90%), the counteranion was exchanged for BArF4 by

exploiting the solubility of NaBArF4 and NaI in dichloromethane, completing the synthesis

of the computationally designed catalyst 5.3. Additionally, the neutral 3,5-

bis(trifluoromethyl) analogue 5.22 was also synthesized in 86% yield by reacting

compound 5.5 with 3,5-bis(trifluoromethyl)phenyl isothiocyanate (5.21, Scheme 5.11).14

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Scheme 5.10. Final transformations to afford mono-charged thiourea catalyst 5.3.

Scheme 5.11. Synthesis of 3,5-bis(trifluoromethyl)-phenyl variant 5.22.

With the desired compound 5.3 in hand, it was employed as a catalyst in the Friedel-

Crafts alkylation between indole 5.23 and trans-β-nitrostyrene 5.24 and compared against

the parent thiourea 5.1 (Table 5.2). As shown in entries 1 and 2, thiourea 5.1 exhibited

better reactivity and selectivity (66% conversion and an er of about 62:38) compared to

the bulkier catalyst 5.3 (38% conversion and 45:55 er). Note the stereochemistry of the

chiral moiety on 5.1 and 5.3 differ at the 1 and 2 positions which led to differing major

enantiomers from the reaction. Since thioureas have been shown to form dimers15 and the

dimerization constants of 5.1 and 5.3 may not be equal, methods to minimize this self-

association were investigated16,17 (for more details, see Chapter 4).

121


Nitrostyrene Catalyzed by Charged Thioureas.a

entry catalyst additive (mol%) Conversion (%)b erc

1 (1S,2R)-5.1 - 66 62.2:37.8 ±0.2

2 (1R,2R)-5.3 - 38 45.2:54.8d

3 (1S,2R)-5.1 HCl (20) 85 79.4:20.6 ±0.0

4 (1R,2R)-5.3 HCl (20) 59 32.8:67.2d

5e (1S,2R)-5.1 mandelic acid (10) 97 81.0:19.0 ±0.1

6e (1R,2R)-5.3 mandelic acid (10) 79 36.9:63.1 ±0.1

a[5.23] = 250 mM, [5.24] = 83 mM. bDetermined from the crude 1H NMR spectrum. cThe given value is the average of 5 measurements and its standard deviation, see ref. 11. dOnly 1 measurement was obtained. e6-Methoxyindole was used instead of indole.

First, 2 equivalents of HCl in relation to the catalyst were employed to disrupt

aggregation of the thiourea molecules (and activate them by hydrogen bonding to the

sulfur atom). The results show the addition of an external acid was beneficial as the

conversions for both catalysts increased by about 20% and the selectivities improved by

over 10% in er (compare entries 1 and 3 and entries 2 and 4). However, the same overall

trend was observed (i.e., 5.1 is a more reactive and selective catalyst than 5.3). Next, the

dependence on the substrate was examined by employing 6-methoxyindole instead of

5.23 (entries 5 and 6), where once again the parent thiourea 5.1 was found to be a more

efficient catalyst compared to 5.3.

Given the unfavorable results in Table 5.2 and that the calculations in Table 5.1 were

performed using 3,5-bis(trifluoromethyl)-phenyl substituted thioureas, it was hypothesized

that the computations did not accurately represent the effect of the N-methylpyridinium

122

ring. That is, the binding of the charged thiourea may be behaving differently than the

proposed neutral analog (Figure 5.2) and/or the presence of the counteranion may be

influencing the actual transition states. Consequently, thioureas 5.22 and 5.2514 were

employed as catalysts to align with the theoretical models and the results are given in

Table 5.3.


Nitrostyrene Catalyzed by Neutral Thioureas.

entry catalyst (mol %) conditionsa conversion (%)b erc

1 (1S,2R)-5.25 (10) A 29 59.6:40.4 ±0.0

2 (1R,2R)-5.22 (10) A 6.6 48.8:51.2 ±0.0

3 (1S,2R)-5.25 (20) B 71 78.1:21.9 ±0.0

4 (1R,2R)-5.22 (20) B 27 39.2:60.8 ±0.0

aMethod A: [5.23] = 250 mM, [5.24] = 83 mM, 10 mol% mandelic acid, 140 h. Method B: [5.23] = 250 mM,

[5.24] = 166 mM, 20 mol% mandelic acid, 96 h. bDetermined from the crude 1H NMR spectrum. cThe given

value is the average of 5 measurements and its standard deviation, see ref 11.

Conditions from Fan’s report2 were used with 10 mol% of mandelic acid in entries 1

and 2, where thiourea 5.25 afforded a 29% conversion and an er of about 60:40 and the

bulkier thiourea 5.22 led to less than 10% conversion and essentially racemic product

(49:51 er). Higher catalyst loading (20 mol%) and more concentrated conditions

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developed by Herrera17a,17b were also explored in entries 3 and 4. Improved reaction rates

(from 29 to 71% conversion for 5.25 and 6.6 to 27% for 5.22) and selectivities (from 60:40

to 78:22 er for 5.25 and 49:51 to 39:61 for 5.22) were achieved for both catalysts. As

shown in Tables 5.2 and 5.3, the experimental results have been contradictory to the

theoretical predictions in Table 5.1.

5.3 Conclusions/Outlook

Due to these initial results, this project was shelved. Future efforts should entail

revisiting the theoretical models to find other transition states. Reactions that require the

alcohol moiety to act only as a hydrogen bond donor to the nucleophile18 and provide no

activation of the electrophile (as in Figure 5.2) may also salvage this computationally

designed thiourea. That is, the loss of reactivity and stereochemical control may have

resulted from poorer interactions of the hydroxyl group with the nitrostyrene and the N-H

bond of the indole due to steric repulsion of the adjacent tert-butyl group. By using a

different nucleophile that would act as the hydrogen bond acceptor with the O-H bond of

the catalyst, a new activation mode may restore or improve the catalytic activity and

stereocontrol (e.g., a 1,4-addition to an α,β-unsaturated carbonyl with a β-keto ester as

shown in Scheme 5.1218b). Additionally, catalysis via anion-binding can also be

examined.19

Lastly, this work has provided a short and efficient blueprint (Scheme 5.8) for the

syntheses of a variety of 2-substituted cis-1-amino-2-indanols, whereby changing the

organometallic reagent used in the first step can lead to new derivatives of thiourea 5.3

(i.e., i-PrMgCl began the route towards the isopropyl variant 5.19).

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Scheme 5.12. A 1,4-addition between a β-keto ester and an α,β-unsaturated carbonyl and

a proposed transition state facilitated by thiourea 5.3.

5.4 Experimental

General. All stir bars, needles, and glassware (vials, NMR tubes, and round-bottomed

flasks) were dried at 120 °C for at least 16 h, and glass syringes were stored in a vacuum

desiccator over Drierite (with colored indicator) for at least 16 h. Molecular sieves and

alumina (neutral, Brockman I, standard grade, 150 mesh, 58 Å) were activated at 300 °C

for at least 24 h. Calcium sulfate and copper (II) sulfate were obtained from Mallinckrodt

and dried at 300 °C for 24 h. Cambridge Isotope Laboratories supplied all of the deuterated

solvents, which were dried with 3 Å molecular sieves for at least 16 h prior to use.

Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (NaBArF4) was obtained from AK

Scientific as a 2.5 hydrate and the water was removed by activated alumina and heating

under reduced pressure as previously described.20,21 Cambridge Isotope Laboratories

supplied all of the deuterated solvents, which were dried with 3 Å molecular sieves for at

least 24 h prior to use. Chloroform (CDCl3) was treated with potassium carbonate and

passed through a column of activated alumina to remove any acid contaminants prior to

storage over 3 Å molecular sieves. 2-Indanone 5.9 was from AK Scientific and the

125

amorphous solid was purified by column chromatography on silica gel (9:1 hexanes/ethyl

acetate) to afford a yellowish-green crystalline material that was stored in a glovebox. 3,5-

Bis(trifluoromethyl)phenyl isothiocyanate 5.21 was used as received from Alfa Aesar. All

other reagents and anhydrous solvents were obtained from Sigma-Aldrich and used

without further purification unless described below. Cerium (III) chloride heptahydrate

(CeCl3.7H2O) was heated at 50 °C (2 h), 60 °C (2 h), 70 °C (2 h), 90 °C (1 h) and 130 °C

(16 h) under high vacuum (0.1 Torr) to afford anhydrous CeCl3 that was stored in a glove

box under N2 atmosphere.5 Tetrahydrofuran (THF) was purified via distillation from a

sodium metal/benzophenone still. p-Toluenesulfonyl isocyanate 5.11 was purified by short

path distillation under reduced pressure (82-83 °C, 0.05 torr).

Bruker Avance III HD 400 or 500 MHz instruments collected all NMR spectra (1H, 13C,

and 19F). Chemical shifts are given in ppm (δ) and 1H and 13C spectral data are referenced

as follows: δ 5.32 and 54.0 (CD2Cl2); 7.26 and 77.2 (CDCl3); 1.94 and 118.3 (CD3CN). All

19F spectra were collected with fluorobenzene as an internal standard (δ -113.78 in

CD2Cl2).22

Thin layer chromatography was carried out with Macherey-Nagel pre-coated TLC

sheets (0.2 mm silica gel with a fluorescent indicator) and visualized using a

phosphomolybdic acid solution and a heat gun. Preparative TLC was accomplished with

SiliCycle SiliaPlate TLC plates (60 Å, 2000 µm). Purification by MPLC was performed on

RediSep Rf gold® (4 or 12 gram) silica gel columns with a CombiFlash® Rf automated

flash chromatography system from Teledyne Isco. Inc. A Thomas Hoover Uni-Melt

apparatus was used to observe uncorrected melting points in unsealed capillaries. FT-IR

spectra were collected with a Thermo Scientific Nicolet iS5 spectrometer with an iD5 ATR

source. High resolution electrospray ionization mass spectra (HRMS-ESI) were obtained

126

with a Bruker ESI-BioTOF instrument using methanolic solutions with polyethylene glycol

internal standards.

The N-methyl-3-pyridiniumisothiocyanate iodide salt 5.4 was prepared following a

previously reported procedure from our laboratory.23 Likewise, 1-(3,5-

bis(trifluoromethyl)phenyl)-3-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thiourea 5.25

was synthesized using a literature procedure24 (see appendix for chapter 4 for spectra).

2-Isopropyl-2-indanol (5.10). Previously reported methods were modified to obtain the

title compound.4 In a 50 mL round-bottomed flask, anhydrous CeCl3 (990 mg, 4.02 mmol)

was stirred vigorously in anhydrous THF (15 mL) overnight under Ar at ambient

temperature. The white CeCl3/THF suspension was then cooled to 0 °C and i-PrMgCl (2.0

M, 2.00 mL, 4.00 mmol) was added dropwise over 2 min, resulting in a brownish gray

emulsion. After stirring 30 min at 0 °C, 2-indanone (5.9, 413 mg, 3.10 mmol) was dissolved

in 6 mL of THF in a separate 6-dram vial under Ar and this solution was added to the

organocerium reagent at 0 °C over 1 h using a syringe pump. The reaction mixture turned

orange and transparent as the ketone reagent was added, and the solution was stirred for

an additional 2 h while warming to room temperature. Thereafter, AcOH (10% v/v in H2O,

20 mL) was used to quench the reaction and the organic layer was separated from the

aqueous layer, and the latter was extracted (3 x 25 mL) by diethyl ether. The combined

organic material was washed with water (30 mL), saturated NaHCO3 (2 x 30 mL), and

brine (30 mL), and then dried over MgSO4. Filtration and removal of the solvent with a

rotary evaporator afforded 650 mg of a yellow oil that crystallized upon standing. A 1H

NMR of the crude material indicated that an 87% conversion to the desired product was

achieved. Purification by MPLC on silica gel with 10% ethyl acetate in hexanes afforded

a clean sample of the desired alcohol as a white solid (mp 57-59 °C), but a significant

127

amount of material was lost during this process. Consequently, the crude product was

carried on into the next step in replicate experiments. 1H NMR (400 MHz, CDCl3) δ 7.25-

7.16 (m, 4H), 3.08 (d, J = 16.4 Hz, 2H), 2.89 (d, J = 16.4 Hz, 2H), 1.93 (septet, J = 6.8 Hz,

1H), 1.57 (s, 1H) 1.06 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 141.7, 126.7,

125.3, 85.3, 45.9, 36.9, 17.8. IR (ATR source) 3540, 3443 cm-1. HRMS-ESI: calcd for

C12H16ONa (M + Na)+ 199.1093, found 199.1087.

(2-Isopropyl)indan-2-yl (4-methylbenzene-1-sulfonyl)carbamate (5.12). Following a

general procedure,6 2-isopropyl-2-indanol 5.10 (210 mg, 1.19 mmol) was dissolved in 1

mL of dichloromethane in a 6-dram vial under Ar at room temperature. Freshly distilled p-

toluenesulfonyl isocyanate 5.11 (180 µL, 232 mg, 1.18 mmol) was added dropwise and

the solution was stirred for 1h, and then diluted with H2O. The reaction mixture was

extracted with dichloromethane (3 x 10 mL) and the combined organic material was

washed with 10% v/v aqueous acetic acid (2 x 20 mL), water (2 x 20 mL), and brine (2 x

20 mL) before being dried over Na2SO4. After filtration, the solvent was removed under

reduced pressure to afford 310 mg (68%) of a white solid (mp 140-142 °C). 1H NMR (400

MHz, C6D6) δ 7.85 (d, J = 8.3 Hz, 2H), 7.00 (dd, J = 3.2 and 5.5 Hz, 2H), 6.87 (dd, J = 3.3

and 5.5 Hz, 2H), 6.65 (d, J = 8.1 Hz, 2H), 3.12 (d, J = 17.4 Hz, 2H), 2.94 (d, J = 17.4 Hz,

2H), 2.69 (septet, J = 6.8 Hz, 1H), 1.79 (s, 3H), 0.59 (d, J = 6.9 Hz, 6H). 13C NMR (100

MHz, C6D6) δ 149.4, 144.1, 140.7, 137.0, 129.5, 128.5, 126.9, 124.4, 97.7, 41.1, 33.2,

21.2, 17.4. IR (ATR source) 3224, 1723, 1699, 1598 cm-1. HRMS-ESI: calcd for

C20H23NSO4Na (M + Na)+ 396.1240, found 396.1251.

(2-Isopropyl)indan-2-yl carbamate (5.14). In a 10-dram vial,7 the crude 2-isopropyl-2-

indanol 5.10 (650 mg) was dissolved in anhydrous CH2Cl2 (4 mL) under Ar at ambient

temperature. Trichloroacetyl isocyanate 5.13 (400 μL, 632 mg, 3.36 mmol) was then

128

added dropwise to the orange solution over 3 min and the reaction mixture was stirred for

4 h at room temperature. The dark red mixture was concentrated to about 1 mL with a

rotary evaporator and then 4 mL of MeOH and K2CO3 (43.0 mg, 0.311 mmol) were added

and stirred vigorously overnight. Saturated aqueous NH4Cl (15 mL) was added, the

aqueous layer was extracted with CH2Cl2 (3 x 20 mL), and the combined organic material

was washed with water (40 mL) and brine (50 mL) before being dried over MgSO4. The

inorganic material was filtered away and the solvent was removed in vacuo to yield 900

mg of a red oily solid. Purification by column chromatography on alumina (Rf = 0.1 in 100%

DCM) afforded 610 mg (89% yield over 2 steps, from 413 mg of 2-indanone 5.9) of a red

solid (mp 103-105 °C). 1H NMR (500 MHz, CDCl3) δ 7.18-7.14 (m, 4H), 4.61 (bs, 2H), 3.36

(d, J = 17.3 Hz, 2H), 3.29 (d, J = 17.2 Hz, 2H), 2.89 (septet, J = 6.8 Hz, 1H), 0.92 (d, J =

7.0 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 156.3, 141.2, 126.6, 124.3, 94.6, 41.3, 33.2,

17.8. IR (ATR source) 3313, 3251, 1670, 1591 cm-1. HRMS-ESI: calcd for C13H17NO2Na

(M + Na)+ 242.1152, found 242.1135.

(±)-cis-8a-Isopropyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (5.15). This

process was accomplished by following the work of Espino and Du Bois.8d In a 25 mL

round-bottomed flask equipped with a reflux condenser, the carbamate 5.14 (211 mg,

0.962 mmol), Rh2(OAc)4 (29.9 mg, 0.0676 mmol), PhI(OAc)2 (450 mg, 1.40 mmol), MgO

(86.4 mg, 2.14 mmol), and a stir bar were added and the atmosphere was purged with Ar.

Anhydrous CH2Cl2 (7 mL) was added and the blue-green reaction mixture was refluxed for

21 h. Upon cooling to room temperature, the brown suspension was filtered through a 0.45

µm syringe filter which was then rinsed with 4 mL of CH2Cl2, and the solvent was removed

with a rotary evaporator. A 1H NMR of the crude material showed >95% of the starting

material was consumed, and a distribution of ~2:1 benzylic amidation (5.15): tertiary

129

amidation (5.18) was obtained. The oily residue was purified by MPLC on silica gel (Rf =

0.45, 3:1 CH2Cl2: ethyl acetate) to afford 101.5 mg (49%) of a red solid (mp 136-137 °C).

1H NMR (500 MHz, CD2Cl2) δ 7.31-7.23 (m, 4H), 6.47 (bs, 1H), 4.89 (s, 1H), 3.30 (s, 2H),

2.10 (septet, J = 6.9 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H). 13C NMR

(125 MHz, CD2Cl2) δ 159.5, 141.6, 140.9, 129.6, 128.2, 125.9, 125.2, 95.9, 63.6, 42.0,

35.9, 17.0, 16.8. IR (ATR source) 3238, 1740, 1707 cm-1. HRMS-ESI: calcd for

C13H15NO2Na (M + Na)+ 240.0995, found 240.0987. HPLC conditions: column =

RegisPack (250 x 4.6 mm, 5 µm) from Regis Technologies, mobile phase = 95:5 hexanes:

isopropanol, flow rate = 2.0 mL min-1, τ1 = 6.7 min, τ2 = 12.2 min.

4',4'-Dimethyl-1,3-dihydrospiro[indene-2,5'-oxazolidin]-2'-one (5.18). This product

(40.4 mg, 20%) was isolated from chromatography on silica gel (Rf = 0.29 in 3:1 CH2Cl2:

ethyl acetate) as a tan solid (mp 200-202 °C). 1H NMR (500 MHz, CDCl3) δ 7.23-7.18 (m,

4H), 5.59 (bs, 1H), 3.27 (d, J = 16.5 Hz, 2H), 3.17 (d, J = 16.6 Hz, 2H), 1.39 (s, 6H). 13C

NMR (100z MHz, CDCl3) δ 158.4, 139.6, 127.1, 124.7, 97.3, 59.0, 40.2, 25.2. IR (ATR

source) 3222, 3118, 2962, 1731 cm-1. HRMS-ESI: calcd for C13H15NO2Na (M + Na)+

240.0995, found 240.0994.

(±)-cis-1-Amino-2-isopropyl-indan-2-ol (5.19). In a 10 mL round-bottomed flask,10 the

isopropyl-oxazolidinone 5.15 (95.0 mg, 0.437 mmol) and KOH (430 mg, 7.66 mmol) were

dissolved in 3 mL of a 1:1 mixture of ethanol and water. The reaction was refluxed for 36

h and upon cooling to room temperature, the solvent was removed with a rotary

evaporator. The solid residue was suspended in 5 mL of water and extracted with ethyl

acetate (3 x 10 mL), and the combined organic material was dried over MgSO4, filtered,

and concentrated. A brown oil was obtained and was purified by MPLC on silica gel (9:1

CH2Cl2: MeOH) to afford 52 mg (62%) of a colorless solid (mp 60-61 °C). 1H NMR (500

130

MHz, CDCl3) δ 7.25-7.20 (m, 4H), 4.33 (s, 1H), 2.99 (d, J = 16.8 Hz, 1H), 2.96 (d, J = 16.9

Hz, 1H), 2.50 (bs, 3H), 1.85 (septet, J = 6.8 Hz, 1H), 1.02 (d, J = 6.8 Hz, 6H). 13C NMR

(125 MHz, CDCl3) δ 144.6, 141.4, 128.0, 126.9, 125.5, 123.6, 82.7, 60.8, 42.2, 36.7, 18.3,

17.7. IR (ATR source) 3379, 3347, 3288, 2960, 2877, 1588 cm-1. HRMS-ESI: calcd for

C12H17NONa (M + Na)+ 214.1202, found 214.1223 and calc for C12H18NO (M + H)+

192.1383, found 192.138.

2-tert-Butyl-2-indanol (5.8). Previously reported methods were modified to obtain the

title compound.4 In a 50 mL round bottomed flask, anhydrous CeCl3 (970 mg, 3.94 mmol)

was stirred vigorously in anhydrous THF (13 mL) overnight under Ar at ambient

temperature. The white suspension was then cooled to -78 °C and tert-butyllithium (1.7 M

in hexanes, 2.10 mL, 3.63 mmol) was added dropwise with a syringe pump over 1 h,

resulting in a bright red-orange mixture that was stirred for an additional 30 min at -78 °C.

In a 6-dram vial, 2-indanone 5.9 (400 mg, 3.03 mmol) was dissolved in 6 mL of THF and

this solution was added to the organocerium reagent with a syringe pump over 2 h at -

78°C. The resulting mixture was allowed to stir another 3 h in the cold and during this time

the bright red-orange color changed to a dull orange-brown. Upon warming to room

temperature, AcOH (10% v/v in H2O, 20 mL) was used to quench the reaction and the

organic layer was collected. The aqueous material was extracted with ethyl acetate (3 x

20 mL) and the combined organic solution was washed with water (40 mL), saturated

NaHCO3 (2 x 40 mL), and brine (40 mL). It was then dried over Na2SO4, filtered, and

concentrated with a rotary evaporator to afforded 470 mg of a yellow oil that crystallized

upon standing and was used in the next step without further purification; in general,

conversions of 25-40% were obtained based upon 1H NMR spectra of the crude material.

For characterization purposes, a purified sample (mp 54-55 °C) was obtained by

131

preparative TLC on silica using CH2Cl2 as the mobile phase (Rf = 0.60). 1H NMR (500

MHz, CD2Cl2) δ 7.23-7.21 (m, 2H), 7.16-7.14 (m, 2H), 3.29 (d, J = 16.5 Hz, 2H), 2.72 (d,

J = 16.5 Hz, 2H), 1.62 (s, 1H, OH), 1.05 (s, 9H). 13C NMR (125 MHz, CD2Cl2) δ 142.4,

126.9, 125.6, 88.1, 43.1, 37.0, 26.2. IR (ATR source) 3470, 2954, 2870 cm-1. HRMS-ESI:

calcd for C13H18ONa (M + Na)+ 213.1250, found 213.1258.

(2-tert-Butyl)-indan-2-yl carbamate (5.7). Following a previously reported procedure,7

the crude alcohol 5.8 (470 mg) was dissolved in anhydrous CH2Cl2 (5 mL) in a 10-dram

vial under Ar at ambient temperature. Trichloroacetyl isocyanate 5.13 (180 μL, 285 mg,

1.51 mmol) was then added dropwise over 2 min to the orange solution and the reaction

was stirred for 2.5 h. Concentration of the resulting dark red mixture to about 1 mL was

carried out with a rotary evaporator and then 4 mL of MeOH and K2CO3 (60 mg, 0.43

mmol) were added and the resulting solution was stirred vigorously overnight. The solvent

was then removed under reduced pressure, and 15 mL of 1 N HCl was added, and the

aqueous solution was extracted with dichloromethane (3 x 15 mL). The combined organic

material was washed with saturated NaHCO3 (2 x 30 mL) and brine (40 mL), and then

dried over MgSO4. Filtration and concentration of the solvent in vacuo afforded 580 mg of

a red oily solid. Purification by column chromatography on silica gel (1:1 hexanes : ethyl

acetate, Rf = 0.47) afforded 243 mg (31% yield over 2 steps) of an amorphous, red

material. 1H NMR (500 MHz, CDCl3) δ 7.13 (s, 4H), 4.48 (bs, 2H, NH2), 3.48 (d, J = 17.6

Hz, 2H), 3.31 (d, J = 17.5 Hz, 2H), 0.98 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 156.2,

141.9, 126.3, 123.7, 94.5, 40.5, 38.6, 24.8. IR (ATR source) 3516, 3368, 2960, 1699, 1583

cm-1. HRMS-ESI: calcd for C14H19NO2Na (M + Na)+ 256.1308, found 256.1312.

(±)-cis-8a-tert-Butyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (5.6). This

process was accomplished by following the work of Espino and Du Bois.8d In a 25 mL

132

round-bottomed flask equipped with a reflux condenser, carbamate 5.7 (204 mg, 0.875

mmol), Rh2(OAc)4 (27.1 mg, 0.0613 mmol), PhI(OAc)2 (395 mg, 1.22 mmol), MgO (81.1

mg, 2.01 mmol), and a stir bar were added, and the atmosphere was purged with Ar.

Anhydrous CH2Cl2 (8 mL) was then added and the blue-green reaction mixture was

refluxed overnight. Upon cooling to room temperature, the brown suspension was filtered

through a 0.45 µm syringe filter (which was rinsed with 4 mL of CH2Cl2) and the solvent

was removed under reduced pressure. The crude residue was subjected to column

chromatography on silica gel (1:3 ethyl acetate: dichloromethane, Rf = 0.54) and 160 mg

(79%) of a red solid (racemic mp 124-129 °C, enantiopure mp 129-130 °C) was obtained.

1H NMR (500 MHz, CD2Cl2) δ 7.32-7.24 (m, 4H), 5.98 (bs, 1H, NH), 4.98 (s, 1H), 3.47 (d,

J = 18.0 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H), 1.04 (s, 9H). 13C NMR (125 MHz, CD2Cl2) δ

159.2, 141.7, 141.1, 129.7, 128.2, 126.0, 125.0, 98.1, 61.8, 41.2, 37.3, 24.5. IR (ATR

source) 3264, 2966, 2874, 1733 cm-1. HRMS-ESI: calcd for C14H17NO2Na (M + Na)+

254.1157, found 254.1147. Analytical HPLC conditions: column = RegisPack (250 x 4.6

mm, 5 µm) from Regis Technologies, mobile phase = 90:10 hexanes : isopropanol, flow

rate = 1.0 mL min-1, τ1 = 6.8 min, τ2 = 10.9 min. Semipreparative HPLC conditions:10 column

= (R,R)-Whelk-O1 (250 x 10.0 mm, 5 µm) from Regis Technologies, mobile phase =

49:49:2 dichloromethane : hexanes : ethanol, flow rate = 2.0 mL min-1. τ1 = 14.5 min, τ2 =

16.6 min.

(1R,2R)-cis-1-Amino-2-tert-butyl-indan-2-ol (5.5). The hydrolysis of both oxazolidinone

enantiomers was accomplished by modifying a previously reported procedure.10 In a 25

mL round-bottomed flask equipped with a reflux condenser, the enantiopure oxazolidinone

5.6 (110 mg, 0.476 mmol) was dissolved in 4 mL of ethanol. Potassium hydroxide (560

mg, 10.0 mmol) and 4 mL of deionized water were added and the mixture was refluxed

133

for 48 hours. Upon cooling to room temperature, the solvent was removed with a rotary

evaporator and the remaining solid residue was suspended in 15 mL of water and

extracted with ethyl acetate (3 x 15 mL). The organic material was combined, dried over

MgSO4, and concentrated under reduced pressure to afford 88.2 mg (90%) of a light

yellow solid (mp 96-98 °C). 1H NMR (500 MHz, CDCl3) δ 7.23-7.20 (m, 4H), 4.54 (s, 1H),

3.21 (d, J = 16.5 Hz), 2.92 (d, J = 17.0 Hz), 2.43 (bs, 3H), 1.01 (s, 9H). 13C NMR (125 MHz,

CDCl3) δ 144.7, 141.9, 128.1, 126.9, 125.5, 123.7, 83.7, 57.9, 40.9, 37.6, 26.0. IR (ATR

source) 3360, 3291, 3113, 2982, 2952, 2910, 2870, 1576 cm-1. HRMS-ESI: calcd for

C13H19NONa (M + Na)+ 228.1358, found 228.1349 and calc for C13H19NOH (M + H)+

206.1539, found 206.1524.

1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-hydroxy-2-tert-butyl-3-dihydro-1H-

inden-1-yl)thiourea (5.22). Following a previously reported procedure,24 (1R,2R)-cis-1-

amino-2-tert-butyl-indan-2-ol 5.5 (40.9 mg, 0.199 mmol) was dissolved in dichloromethane

(1 mL) under inert atmosphere in a 6-dram vial. 3,5-Bistrifluoromethylisothiocyanate 5.21

(40.0 µL, 59.4 mg, 0.219 mmol) was then added dropwise and the reaction was stirred

overnight at room temperature. The solvent was removed with a rotary evaporator and the

remaining oily solid residue was purified by column chromatography on silica to afford

82.0 mg (86%) of a colorless, shiny solid (mp 87-89 °C). 1H NMR (500 MHz, CD2Cl2) δ

8.57 (s, 1H), 7.83 (s, 2H), 7.68 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.30-7.29 (m, 1H), 7.12

(s, 3H), 6.29 (d, J = 8.8 Hz, 1H), 3.42 (d, J = 17.0 Hz, 1H), 2.77 (d, J = 17.1 Hz, 1H), 2.08

(bs, 1H), 1.14 (s, 9H). 13C NMR (125 MHz, CD2Cl2) δ 180.0, 142.0, 139.34, 139.29, 133.1

(q, J = 33.6 Hz), 128.7, 127.6, 125.6, 125.1, 123.9, 123.5 (q, J = 273 Hz), 119.5 (septet, J

= 3.6 Hz), 89.5, 62.6, 42.6, 37.5, 26.3. 19F NMR (376 MHz, CD2Cl2) δ -63.3. IR (ATR

134

source) 3364, 3240, 2964, 1525, 1275, 1129 cm-1. HRMS-ESI: calcd for C22H22N2F6OSNa

(M + Na)+ 499.1249, found 499.1263.

3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium

iodide.2 In a 6-dram vial under inert atmosphere, (1S,2R)-cis-1-amino-2-indanol (100 mg,

0.673 mmol) and N-methyl-3-pyridiniumisothiocyanate iodide 5.4 (184 mg, 0.661 mmol)

were dissolved in 6 mL of anhydrous acetonitrile (where a colorless precipitate formed

immediately) and the suspension was stirred overnight. Diethyl ether (15 mL) was added

in one portion and stirred for 5 min before the solid was allowed to settle to the bottom of

the vial and the supernatant was removed by syringe. The precipitate was washed with

additional diethyl ether (4 x 10 mL) and dried with a rotary evaporator followed by

mechanical pump to afford 249 mg (88%) of an off-white solid that gave a 1H spectrum

that was in accord with a previous report.2

3-(3-((1R,2R)-2-Hydroxy-2-tert-butyl-3-dihydro-1H-inden-1-yl)thioureido)-1-

methylpyridinium iodide (5.20). In a 6-dram vial under inert atmosphere, (1R,2R)-cis-1-

amino-2-tert-butyl-indan-2-ol 5.5 (41.1 mg, 0.200 mmol) and N-methyl-3-

pyridiniumisothiocyanate iodide 5.4 (55.4 mg, 0.199 mmol) were dissolved in 2 mL of

anhydrous acetonitrile and the reaction mixture was stirred overnight. The solvent was

removed under reduced pressure and the remaining solid residue was dissolved in 1 mL

of acetonitrile and added dropwise into 15 mL of stirring anhydrous diethyl ether. An off-

white precipitate formed immediately and was allowed to settle to the bottom of the vial

and the supernatant was removed by syringe. The solid was washed with additional diethyl

ether (4 x 10 mL) and dried with a rotary evaporator followed by mechanical pump to afford

86.9 mg (90%) of a yellow solid (mp 158-160 °C). 1H NMR (500 MHz, CD2Cl2) δ 11.23 (bs,

1H), 9.97 (s, 1H), 8.94 (d, J = 11.2 Hz, 1H), 8.47 (d, J = 11.5 Hz, 1H), 8.25 (d, J = 7.5 Hz,

135

1H), 7.73 (dd, J = 7.4 and 10.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.21-7.15 (m, 3H), 6.22

(d, J = 11.5 Hz, 1H), 4.23 (s, 3H), 3.29 (d, J = 20.8 Hz, 1H), 2.86 (d, J = 21.0 Hz, 1H), 2.75

(bs, 1H), 1.10 (s, 9H). 13C NMR (125 MHz, CD2Cl2) δ 180.5, 142.33, 142.28, 140.4, 137.9,

136.1, 135.6, 128.4, 127.9, 127.3, 125.6, 125.0, 89.8, 61.8, 49.9, 41.6, 37.4, 26.6. IR (ATR

source) 3406, 3250, 3025, 2954, 1636, 1603, 1576, 1501, 1228, 1168 cm-1. HRMS-ESI:

calcd for C20H26N3OS (M – I-)+ 356.1791, found 356.1786.

General anion-exchange procedure.

In a 6-dram vial under inert atmosphere, sodium tetrakis(3,5-

bis(trifluoromethyl)phenyl)borate and the corresponding iodide salt were stirred in CH2Cl2

overnight. A white precipitate formed and the reaction mixture was filtered through a 0.45

µm PTFE syringe filter, which was then washed with additional DCM. The mixture was

concentrated under reduced pressure and the remaining solid residue was dissolved in

DCM and dried over CaSO4. The filtration process was repeated and the solvent was

removed with a rotary evaporator followed by a mechanical pump.

3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (5.1).2 Sodium tetrakis(3,5-

bis(trifluoromethyl)phenyl)borate (188 mg, 0.212 mmol) and 3-(3-((1S,2R)-2-hydroxy-2,3-

dihydro-1H-inden-1-yl)thioureido)-1methylpyridinium iodide (81.3 mg, 0.190 mmol) in 4

mL of DCM afforded 221 mg (100%) of a fluffy, light yellow solid that gave a 1H spectrum

that was in accord with a previous report2 (see the appendix for chapter 4 for spectra).

3-(3-((1R,2R)-2-Hydroxy-2-tert-butyl-3-dihydro-1H-inden-1-yl)thioureido)-1-

methylpyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (5.3). Sodium

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (175 mg, 0.198 mmol) and 3-(3-((1R,2R)-2-

136

hydroxy-2-tert-butyl-3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium iodide 5.20

(86.9 mg, 0.180 mmol) in 3 mL of DCM afforded 200 mg (91%) of a fluffy, light yellow solid

(mp 61-63 °C). 1H NMR (500 MHz, CD3CN) δ 9.50 (s, 1H), 8.97 (bs, 1H), 8.45 (d, J = 8.7

Hz, 1H), 8.29 (d, J = 5.9 Hz, 1H), 7.88 (dd, J = 6.3 and 8.3 Hz, 1H), 7.76 (d, J = 8.0 Hz,

1H), 7.69 (s, 8H), 7.67 (s, 4H), 7.30 (d, J = 7.3 Hz, 1H), 7.27-7.20 (m, 3H), 6.15 (d, J = 8.5

Hz, 1H), 4.28 (s, 3H), 3.39 ((d, J = 16.9 Hz, 1H), 3.28 (s, 1H), 2.85 (d, J = 16.9 Hz, 1H),

1.08 (s, 9H). 13C NMR (125 MHz, CD2Cl2) δ 179.3, 162.3 (q, 1JB-C = 50.4 Hz), 141.7, 141.3,

139.5, 138.4, 138.1, 136.9, 135.4, 129.4 (qq, 3JB-C = 3.1 Hz and 2JF-C = 32.0 Hz), 129.2,

128.7, 127.8, 126.1, 125.2 (q, 1JF-C = 273 Hz), 125.1, 118.1 (septet,25 3JF-C = 4.0 Hz), 88.7,

62.4, 50.1, 42.7, 37.5, 26.2. 19F NMR (376 MHz, CD2Cl2) δ -62.8. IR (ATR source) 3332,

3085, 2970, 1610, 1507, 1354, 1273, 1112 cm-1. HRMS-ESI: calcd for C20H26N3OS (M –

C32H12BF24-)+ 356.1791, found 356.1786.

General Procedure of the Friedel-Crafts reaction between indole and trans-β-

nitrostyrene in Table 5.2.

In a 6-dram vial under inert atmosphere, 5.0 µmol of catalyst and the chosen amount

of external Brønsted acid were added and dissolved in 300 µL of the reaction solvent. A

separate 2-dram vial was charged with 0.150 mmol of indole 5.23 and 0.050 mmol of

trans-β-nitrostyrene 5.24 under inert atmosphere and 300 µL of solvent was added. Both

vessels were cooled to the desired temperature before the entire indole solution was

transferred to the vial containing the catalyst via syringe over 10 s. The contents were then

shaken and allowed to react for 48 h. An aliquot of the reaction mixture at various times

was diluted with CDCl3 and a 1H NMR spectrum was obtained to calculate the percent

conversion to the desired product. The remaining material was subjected to MPLC on

silica gel (100% hexanes for 1 min followed by an 8 min linear gradient to 100% CH2Cl2)

137

to isolate the product for chiral HPLC analysis with a RegisCell column (75:25 hexanes /

isopropanol, 1.0 mL min-1, τmajor = 17.3 min, τminor = 20.0 min, λ = 280, 220, and 230 nm).11,26

138

Chapter 6: Electrostatically-Enhanced BINOL Hydrogen Bonding Catalysts

6.1 Introduction

Brønsted acid organocatalysts have received significant attention over the past two

decades.1,2 These small, metal-free molecules are generally more sustainable and less

toxic than their inorganic counterparts. A variety of hydrogen bond donors have been

studied such as (thio)ureas,3,4 phosphoric acids,5 squaramides,6 silanediols,7 α,α,α’,α’-

tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs),8 and guanidinium ions.9 These

organocatalysts can facilitate a wide array of chemical transformations and current

research focuses on improving their reactivities, thereby lowering their catalyst

loadings.10,11

Previous findings in this field have shown that the strength of the Brønsted acid

typically correlates with its reactivity.12 That is, use of a more acidic catalyst generally

results in faster reaction rates. Thus, electron-withdrawing substituents are commonly

installed into the catalyst framework.10 The bis(3,5-trifluoromethyl)phenyl moiety is the

most widely used group and is regarded as a privileged substituent in Brønsted acid

organocatalysis.13,14

More recently, the Kass group has shown that N-methylpyridinium centers significantly

enhance the reactivities of hydrogen bond donors in nonpolar media.15 Efforts to further

improve this effect have been investigated through protonated,16 N-vinyl, and N-

arylpyridinium variations.17 This electrostatically-enhanced design has also been

successfully utilized with achiral and chiral thioureas18–21 and phosphoric acids.22–24

Ongoing research continues to explore this methodology with other catalyst frameworks.

139

A commonly used skeletal structure is the 1,1’-bi-2-naphthol (BINOL, 6.1) moiety

which has been popularized in ligands for metal centered catalysis25–27 and has recently

been exploited with a number of organocatalysts.28–31 This framework provides a rigid,32

axis of chirality and can be substituted in a variety of positions.25 The 3 and 3’-positions

are most commonly exploited since substituents at these positions have been shown to

influence the reactivities and selectivities of Brønsted acid organocatalysts that bear this

scaffold (6.2, Scheme 6.1).33,34 BINOL itself, however, has been largely overlooked as a

hydrogen bond catalyst due to its relatively weak acidity,35 and stronger acids like

phosphoric acid 6.3 can be made from them in one step with phosphoryl chloride (POCl3,

Scheme 6.1).34

Scheme 6.1. BINOL derivatives.

Given the lack of research on BINOL and its substituted derivatives as hydrogen bond

catalysts, this platform represents an attractive area for further exploration, particularly

with positively charged substituents at the 3 and 3’-positions (Figure 6.1). In this chapter,

efforts to synthesize a variety of pyridinium BINOL organocatalysts (such as 6.4) are

presented. Chemical transformations that are of interest are also outlined.

140

Figure 6.1. Generic charge-enhanced BINOL catalysts.


3,3’-Substituted BINOLs are most commonly synthesized by first installing synthetic

handles such as halogens or boronic esters in these positions.25,34 Thus, a variety of cross-

coupling reactions can then be exploited to afford a variety of derivatives. Following this

synthetic route, (R)-BINOL (6.1) was first protected with a methoxy ethyl ether (MOE,

Scheme 6.2).22,36 This process was accomplished with sodium hydride and chloromethyl

ethyl ether in DMF and afforded a quantitative yield of the desired compound 6.5.

Following a literature procedure,36 the subsequent ortho-lithiation with n-BuLi and trapping

with iodine afforded the protected 3,3’-diiodo BINOL 6.6. Initial efforts included adding

THF at room temperature prior to addition of iodine,37 which resulted in about a 40% yield

of the desired compound. By omitting the THF entirely, the yield of intermediate 6.6 was

essentially doubled (75%).36 The first two steps were successfully scaled up to afford

almost 9 g of the 3,3’-diiodo compound 6.6 and no chromatography was required to obtain

pure samples of 6.5 and 6.6.

141

Scheme 6.2. Synthesis of diiodo-intermediate 6.6.

The diiodo-BINOL intermediate 6.6 was then employed in palladium-catalyzed cross

coupling reactions to afford 3,3’-dipyridyl frameworks (Scheme 6.3). A Suzuki-Miyaura

cross coupling with 3-pyridyl boronic acid (6.7) afforded the 3,3’-di(3-pyridyl) compound

6.8, which was subsequently deprotected with HCl to afford the 3,3’-di(3-pyridyl) BINOL

6.9 (71% yield over two steps).22,38 Since the position of the charge center in relation to

the ionization site has been shown to affect the reactivities of hydrogen bond donors,16 the

3,3’-di(2-pyridyl) BINOL 6.10 was another desired catalyst scaffold. This compound was

obtained in 62% yield via a Negishi cross coupling with 2-bromopyridine (6.11) followed

by acid-mediated hydrolysis of the MOE protecting group.39 The MOE-protected BINOL

intermediate 6.12 was not isolated since 3,3’-di(2-pyridyl) BINOL 6.10 was present in the

crude mixture of the cross-coupling, indicating the protecting group was cleaved under the

Negishi reaction conditions. Thus, the material was carried forward without further

purification.

Positively charged centers were first introduced through N-alkylpyridinium rings by

exposing the 3,3’-dipyridyl BINOLs 6.9 and 6.10 to 1-iodooctane or iodomethane.22 The

doubly charged iodide intermediates (6.13 and 6.14 where R = C8H17 and CH3,

respectively) from 3,3’-di(3-pyridyl)-BINOL 6.9 were obtained in good yields (84 and 89%,

Scheme 6.4). Anion exchange for the weakly coordinating BArF4 anion was facilitated by

142

the differing solubilities of NaI and NaBArF4 in dichloromethane, affording the final catalysts

6.15 and 6.16 in excellent yields (≥95%).

Scheme 6.3. Cross coupling reactions to synthesize 3,3’-di(3-pyridyl) and 3,3’-di(2-

pyridyl) BINOL s.

Scheme 6.4. Synthesis of 3,3’-di(N-alkyl-3-pyridinium)-BINOLs.

143

The 3,3’-di(2-pyridyl) BINOL 6.10, however, was resistant to these alkylation

conditions. A possible explanation for the lack of reactivity is the presence of an

intramolecular hydrogen bond between the O-H groups and the pyridine nitrogen atoms

(Scheme 6.5), thereby reducing the latter’s nucleophilicity and slowing the desired

reaction. More active alkylating agents such as dimethyl sulfate, trimethyloxonium

tetrafluoroborate, and methyl triflate have been employed and these reagents resulted in

complex mixtures. Conditions to obtain compound 6.17 are still being optimized.

Scheme 6.5. Attempts to alkylate BINOL 6.10 and a proposed intramolecular interaction

that prevents this type of transformation.

If necessary, an alternative route to acquire compound 6.17 can be envisioned

(Scheme 6.6). The presence of a base such as K2CO3 would deprotonate the hydroxyl

groups and upon exposure to methyl iodide, methylation of the nitrogen and oxygen atoms

should occur to afford doubly charged intermediate 6.17. Subsequent deprotection of the

aryl methoxy ethers with BBr3 would afford halide salt 6.18 which could undergo anion

exchange with NaBArF4 in dichloromethane. Alternatively, the MOE-protected BINOL 6.12

could be isolated after the Negishi cross coupling (Scheme 6.3), alkylated with

iodomethane, and then deprotected with HCl to acquire BINOL 6.18.

144

Scheme 6.6. Potential routes to synthesize iodide salt 6.18.

Protonated pyridinium centers have been shown to improve reactivity over their

corresponding N-alkylated analogues.16 They also introduce additional hydrogen bond

donating sites that could to more rigid structures and greater reaction selectivities.

Consequently, protonated BINOLs are of interest and efforts have been taken to

synthesize these compounds. Use of concentrated HCl to protonate 3,3’-di(3-pyridyl)-

BINOL 6.9 afforded the desired chloride salt 6.20 (Scheme 6.7), but decomposition and

incomplete anion exchange with the weakly coordinating BArF4 anion (6.21) was

encountered in the following step.

Scheme 6.7. Initial attempt at the synthesis of BINOL 6.21.

145

It was hypothesized that the water in the concentrated HCl was the cause of these

complications,16 so anhydrous trifluoromethanesulfimide ((CF3SO2)2NH, Tf2NH) was used

to protonate both 3,3’-dipyridyl-BINOL isomers 6.9 and 6.10 (Scheme 6.8). The protonated

compounds 6.22 and 6.23 were isolated in excellent yield (91 and 93%). Anion exchange

of the bis(trifluoromethanesulfonyl)imide (Tf2N) ion for BArF4 is required to complete the

synthesis of the desired salts 6.21 and 6.24, and such transformation on different salts

has been previously carried out.16,19,22

While dealing with the synthetic endeavors above, the completed 3,3’-di(N-alkyl-3-

pyridinium)-BINOLs 6.15 and 6.16 were employed as catalysts in the Friedel-Crafts

alkylation between indole (6.25) and trans-β-nitrostyrene (6.26, Table 6.1). In both cases,

slow reactions (< 10% conversion after 64 h) and racemic products resulted.

Scheme 6.8. Progress towards protonated BINOLs 6.21 and 6.24.

146

Table 6.1. Asymmetric Friedel-Crafts Reaction Catalyzed by Charged BINOLs.

6.3 Future Work/Outlook

First, the syntheses of the N-alkylated and protonated pyridinium compounds need to

be completed. Also, phosphonium derivatives (6.29) can be explored (Scheme 6.9). This

strategy was found to be an effective way to electrostatically enhance BINOL-based

phosphoric acids (6.28),22,23 and charged-BINOL halide salts (6.27) were synthesized as

intermediates in those reports. Thus, anion exchange with NaBArF4 in dichloromethane

would be the only new step required to synthesize this type of BINOL catalyst (6.29).

entry catalyst time (h) conv. (%)b ee (%)c

1 6.15 64 9 0

2 6.16 65 8 0

a[6.24] = 250 mM. [6.25] = 83 mM. bCalculated from a 1H NMR spectrum of the reaction mixture. cObtained by HPLC with a chiral column.

147

Scheme. 6.9. Synthesis of phosphonium ion-tagged BINOL catalysts.

Once the desired catalysts have been acquired, their reactivities and selectivities

should be examined for variety of transformations and compared to their neutral

analogues. The Friedel-Crafts alkylation of indole (6.25) with trans-β-nitrostyrene (6.26,

Table 6.1) has been examined with every catalyst prepared in the Kass group and thus

serves as a useful test-bed transformation. Non-charged BINOLs have been reported to

catalyzed Baylis-Hillman reactions between α,β-unsaturated ketones such as cyclohe-2-

en-1-one (6.30) and aldehydes (6.31) in the presence of trialkylphosphines (Scheme

6.10).40,41 To obtain good yields and high selectivities, reduced temperatures and long

reaction times of 48 h were required. A potential complication with this reaction is an

interaction of the nucleophilic cocatalyst (e.g., Et3P) with the BINOL, leading to

deactivation. Thus, a delicate balance will need to be struck between its steric bulk and

nucleophilicity to carry out this transformation.

148

Scheme 6.10. Asymmetric Morita-Baylis-Hillman reactions catalyzed by BINOL

hydrogen bonding catalysts.

Additionally, a tandem N-nitroso aldol and Michael addition transformation between

dienamine 6.32 and nitrosobenzene (6.33) leading to a heterocyclic bicycle (Scheme 6.11)

is an interesting process to explore.42 A high catalyst loading (30 mol%) and prolonged

reaction times of 12 – 24 h were required for neutral BINOL catalysts, and hopefully lower

loadings and shorter times can successfully be employed with charged variants.

Scheme 6.11. N-Nitroso aldol/Michael addition catalyzed by BINOL derivatives.

Lastly, reactions that have been catalyzed by other chiral diols43 such as TADDOLs

should be investigated.8 In particular, reactions that include substrates with acid labile

functional groups would expand the utility of these BINOL catalysts. For example, a

hetero-Diels-Alder cycloaddition44,45 between Rawal’s diene that contains a silyl enol ether

(6.34) and an aldehyde (6.31, Scheme 6.12) would showcase a large functional group

tolerance by these catalysts.

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Scheme 6.12. A hetero-Diels Alder cycloaddition catalyzed by TADDOLs.

6.4 Experimental

General. All reaction glassware (vials, NMR tubes, flasks) and stir bars were dried in an

oven (120 °C) for at least 16 h, and glass syringes and volumetric flasks were stored in a

vacuum desiccator over Drierite for at least 16 h. Alumina (neutral, Brockman I, standard

grade, 150 mesh, 58 Å) and 3 Å molecular sieves were activated at 300 °C for at least 24

h. Deuterated solvents came from Cambridge Isotope Laboratories and were stored over

3 Å molecular sieves for at least 24 h prior to use.

Concentrated HCl (37%) was obtained from VWR International. 3-Pyridyl boronic acid

was from Matrix Scientific. Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate

(NaBArF4) was obtained as a 2.5 hydrate (based on its 1H NMR spectrum) from AK

Scientific and the water was removed by running the material through a column of

activated alumina followed by heating under reduced pressure as previously described.1,2

All other chemicals and anhydrous solvents were purchased from Sigma Aldrich and used

as received without further purification except THF, which was purified via distillation from

a sodium metal/benzophenone still, and 2-bromopyridine, which was purified and dried by

a column of activated alumina and stored over 3 Å molecular sieves for 16 h prior to use.

Bruker Avance III HD 400 or 500 MHz instruments were used to collect 1H, 13C, and

19F NMR spectra. All chemical shifts are reported in ppm (δ) and 1H and 13C spectral data

are referenced as follows: δ 7.26 and 77.0 (CDCl3); 5.32 and 53.8 (CD2Cl2); 1.94 and

150

118.3 (CD3CN); 2.50 and 39.5 (d6-DMSO). Fluorobenzene was used as an internal

standard for all 19F spectra (δ -113.78 in CD2Cl2; -114.81 in CD3CN).3

TLC analyses were performed with Merck precoated 250 nm silica gel 60 F-254 plates

and visualized with a hand held UV lamp. Flash chromatography was performed with a

Combiflash® Rf automated flash chromatography system with silica gel columns.

Uncorrected melting points were observed using a Thomas Hoover Uni-Melt apparatus

with unsealed capillary tubes. FT-IR data for characterization were collected with a

Thermo Scientific Nicolet iS5 spectrometer with an iD5 ATR source. High resolution

electrospray ionization mass spectra (HRMS-ESI) were obtained with a Bruker ESI-

BioTOF instrument from methanol solutions and polyethylene glycol as an internal

standard.

(R)-2,2′-Bis(ethoxymethoxy)-1,1′-binaphthyl (6.5).4 In a 100 mL round-bottomed flask,

a stir bar and NaH (5.55 g of a 60% w/w oil dispersion corresponding to 3.33 g of NaH or

139 mmol) were added and the atmosphere was purged with argon. Pentane (20 mL) was

added and stirred for 5 min and the supernatant was removed by syringe and this process

was repeated 2 more times before cooling in a water/ice bath. In a separate 100 mL round-

bottomed flask, (R)-2,2’-dihydroxy-1,1’-binaphthyl 6.1 (5.16 g, 18.0 mmol) was dissolved

in DMF (40 mL) under argon and this solution was added dropwise into the NaH containing

flask over 20 min at 0 °C. The resulting green mixture was stirred for an additional 10 min

at this temperature before adding chloromethyl ethyl ether (4.20 mL, 4.28 g, 45.3 mmol)

dropwise over 10 min and the solution was maintained at 0 °C for an additional 30 min.

The water/ice bath then was removed and the flask was allowed to warm to room

temperature over a 3 h period while stirring. Water (20 mL) was added to quench the

reaction and the resulting solution was extracted with diethyl ether (3 x 70 mL). The

151

combined organic material was then washed with water (3 x 50 mL), saturated NaHCO3

(1 x 50 mL), and brine (1 x 70 mL) before drying over MgSO4. Filtration and concentration

with a rotary evaporator afforded a cloudy-white viscous oil (7.98 g) that passed through

a plug of silica gel with benzene. Removal of the volatiles under reduced pressured yielded

7.14 g (99%) of a clear, colorless viscous oil that provided spectra in accord with a

previous report from our laboratory.4 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.0 Hz,

2H), 7.87 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.34 (ddd, J = 8.1, 6.8, 1.3 Hz, 2H),

7.21 (ddd, J = 7.9, 6.6, 1.2 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.13 (d, J = 6.8 Hz, 2H), 5.02

(d, J = 7.0 Hz, 2H), 3.49 – 3.21 (m, 4H), 1.00 (t, J = 7.1 Hz, 6H).

(R)-3,3′-Diiodo-2,2′-bis(ethoxymethoxy)-1,1′-binaphthyl (6.6). This process was

accomplished by following a previously reported procedure.5 In a two-neck, 500 mL round-

bottomed flask, (R)-2,2′-bis(ethoxymethoxy)-1,1′-binaphthyl 6.5 (7.14 g, 17.8 mmol) was

dissolved in diethyl ether (300 mL) under inert atmosphere at ambient temperature and n-

BuLi (2.5 M in hexane, 22.0 mL, 53.3 mmol) was added dropwise over 20 min. The

resulting mixture was stirred at room temperature for 3 h and a gray precipitate formed.

After cooling to -78 °C, solid I2 (13.5 g, 53.3 mmol) was added in one portion and the

reaction was stirred for 1 h before warming to room temperature. The solution turned bright

orange-red and was stirred an additional 2 h before quenching with saturated aqueous

NH4Cl (100 mL). The ethereal layer was collected and the aqueous phase was extracted

with ethyl acetate (2 x 100 mL), and the combined organic material was washed with

saturated Na2SO3 (2 x 100 mL), saturated NaHCO3 (2 x 100 mL), and brine (1 x 200 mL)

prior to drying over MgSO4. Filtration of the inorganic material and concentration of the

solvent with a rotary evaporator afforded an orange, oily residue (11.8 g) that was stirred

in MeOH (100 mL) overnight at room temperature. An off-white solid in a reddish-orange

152

solution resulted and the insoluble material was collected by vacuum filtration and washed

with additional MeOH to afford 8.71 g (75%) of a beige powder (mp 97-99 °C). 1H NMR

(400 MHz, CD2Cl2) δ 8.57 (s, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.30

(t, J = 7.4 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 4.85 (d, J = 5.5 Hz, 2H), 4.65 (d, J = 5.5 Hz,

2H), 3.02 (dq, J = 9.5, 7.1 Hz, 2H), 2.71 (dq, J = 9.4, 7.0 Hz, 2H), 0.65 (t, J = 7.1 Hz, 6H).

13C NMR (100 MHz, CD2Cl2) δ 152.7, 140.6, 134.4, 132.9, 127.6, 127.5, 126.9, 126.6,

126.3, 98.6, 93.3, 65.5, 14.8. IR (ATR source) 2981, 1569, 1559 cm-1. HRMS-ESI: calcd

for C26H24I2O4Na (M + Na)+ 676.9656, found 676.9669.

(R)-3,3′-Di(3-pyridyl)-2,2′-dihydroxyl-1,1′-binaphthyl (6.9).4,6 This process was

accomplished by following a similar procedure reported from our laboratory.4 1,2-

Dimethoxy ether (DME) was degassed by bubbling a stream of argon through it for 1 hour.

In a 25 mL round-bottomed flask equipped with a reflux condenser, (R)-3,3′-diiodo-2,2′-

bis(ethoxymethoxy)-1,1′-binaphthyl 6.6 (500 mg, 0.764 mmol), 3-pyridyl boronic acid 6.7

(357 mg, 2.90 mmol), Pd(PPh3)4 (99.0 mg, 0.0857 mmol), and a stir bar were added and

the atmosphere was purged with argon. Then 5 mL of DME and 2 mL of 2M Na2CO3 in

water were added by syringe and the mixture was refluxed overnight. Upon cooling to

room temperature, the solvent was removed under reduced pressure and saturated NH4Cl

was added. Dichloromethane was used to extract the aqueous layer (3 x 30 mL) and the

combined organic material was washed with saturated NH4Cl and brine prior to drying

over Na2SO4. Filtration and removal of the solvent with a rotary evaporator afforded a

yellow gummy residue that was purified by MPLC on silica gel (100% ethyl acetate). The

resulting yellow solid (580 mg) was dissolved in 7 mL of ethanol and 2 mL of concentrated

HCl was added in one portion and the mixture was stirred for 3 h at ambient temperature,

resulting in a white precipitate in a yellow supernatant. Saturated NaHCO3 (25 mL) was

153

added to neutralize the solution and extraction with dichloromethane (3 x 20 mL) was

performed. The combined organic material was washed with water and brine before drying

over MgSO4. Removal of the volatiles in vacuo afforded a yellow solid that was dissolved

in boiling chloroform (5 mL) and added dropwise into 15 mL of hexanes while stirring. The

resulting precipitate was collected by vacuum filtration and washed with hexanes to afford

227 mg (67%) of a white solid that afforded spectra in accord with previous reports.4 1H

NMR (400 MHz, CDCl3) δ 11.62 (s, 2H), 9.21 (d, J = 1.7 Hz, 2H), 7.68 (dt, J = 7.8 and 1.6

Hz, 2H), 7.55 (dd, J = 6.6, 2.0 Hz, 2H), 7.31-7.22 (m, 6H), 7.14 (s, 2H), 6.70 (dd, J = 7.8

and 5.0 Hz, 2H), 6.55 (dd, J = 4.8 and 1.2 Hz, 2H).

(R)-3,3′-Di(2-pyridyl)-2,2′-dihydroxyl-1,1′-binaphthyl (6.10).5,7 This transformation was

accomplished by following a literature procedure.7 In a 3-neck 100 mL round-bottomed

flask equipped with a reflux condenser, (R)-3,3′-diiodo-2,2′-bis(ethoxymethoxy)-1,1′-

binaphthyl 6.6 (485 mg, 0.742 mmol) was dissolved in 5 mL of THF under an inert

atmosphere. The flask was then cooled with a dry ice/acetone bath and t-BuLi (1.7 M in

hexanes, 2 mL, 3.4 mmol) was added dropwise over 2-3 min, and the resulting cloudy

yellow mixture stirred for 15 min. In a 6-dram vial, anhydrous ZnCl2 (215 mg, 1.58 mmol)

was dissolved in 2 mL of THF and this solution was then dropwise over 2-3 min into the

3-neck flask at -78 °C. The reaction was stirred at this temperature for 30 min before

allowing it to warm to room temperature by removing the dry ice/acetone bath. In a

separate 6-dram vial, Pd(PPh3)4 (86 mg, 0.0744 mmol) was dissolved in 4 mL of THF and

then added to the reaction flask in one portion. 2-Bromopyridine 6.11 (220 µL, 365 mg,

2.31 mmol) was subsequently added in one portion and the resulting mixture was refluxed

overnight. Upon cooling to room temperature, the solvent was removed by rotary

evaporation and 30 mL of a saturated NH4Cl solution was added to the residue. Extraction

154

with dichloromethane (2 x 30 mL) was carried out and the organic matieral was washed

with NH4Cl (30 mL) and brine (50 mL) prior to drying over MgSO4. Filtration and

concentration of the volatiles under reduced pressure afforded a gummy yellow residue

(~770 mg) that was dissolved in 5 mL of methanol. Concentrated HCl (2 mL) was added

dropwise over 1 min and the mixture stirred for 3 h at ambient temperature. Saturated

NaHCO3 solution (25 mL) was added and the resulting suspension was extracted with

dichloromethane (3 x 20 mL). The organic material was washed with brine (50 mL), dried

over MgSO4, and concentrated in vacuo to afford a yellow oil. This material was dissolved

in 2 mL of dichloromethane and added dropwise into 15 mL of methanol with stirring. A

yellow precipitate was produced and collected by vacuum filtration to afford 203 mg (62%)

of the desired compound that provided spectra in accord with previous reports.5,7 1H NMR

(400 MHz, CD2Cl2) δ 14.26 (s, 2H), 8.56 (s, 2H), 8.50 (d, J = 4.3 Hz, 2H), 8.29 (d, J = 8.3

Hz, 2H), 8.02 – 7.92 (m, 4H), 7.44 – 7.09 (m, 8H).

(R)-3,3′-Di(3-N-octylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl iodide (6.13). In a 25

mL round-bottomed flask equipped with a reflux condenser under argon, (R)-3,3′-di(3-

pyridyl)-2,2′-dihydroxyl-1,1′-binaphthyl 6.9 (153 mg, 0.347 mmol) and a stir bar were

added along with 10 mL of anhydrous acetonitrile. 1-Iodooctane (250 µL, 334 mg, 1.39

mmol) was added by syringe in one portion and the resulting suspension was refluxed

overnight, resulting in a homogenous orange mixture. Upon cooling to room temperature,

the solvent was removed with a rotary evaporator and the remaining solid residue was

dissolved in minimal acetonitrile and added dropwise to 15 mL of diethyl ether while

stirring. A gray precipitate formed and the suspension was stirred for 15 min before

collecting the insoluble material by vacuum filtration. The solid was washed with additional

diethyl ether and then hexanes prior to drying under reduced pressure (0.05 torr) to afford

155

283 mg (89%) of a beige solid that provided spectra in accord with a previous report,4 and

was stored in a glovebox. 1H NMR (400 MHz, CD2Cl2) δ 10.06 (s, 2H), 8.81 (d, J = 6.4 Hz,

4H), 8.32 (s, 2H), 8.10 (t, J = 7.1 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H),

7.34 (t, J = 7.3 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.56 (bs, 2H), 4.84 – 4.66 (m, 4H), 2.07

(dq, J = 14.9, 7.0 Hz, 4H), 1.57 – 1.12 (m, 20H), 0.83 (t, J = 6.6 Hz, 6H).

(R)-3,3′-Di(3-N-methylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl iodide (6.14). In a

10 mL round-bottomed flask equipped with a reflux condenser under argon, (R)-3,3′-di(3-

pyridyl)-2,2′-dihydroxyl-1,1′-binaphthyl 6.9 (52.8 mg, 0.120 mmol) and a stir bar were

added and along with 4 mL of anhydrous acetonitrile. Iodomethane (50.0 µL, 114 mg,

0.803 mmol) was syringed into the flask in one portion and the resulting suspension was

refluxed overnight. This led to a homogenous orange mixture which was concentrated with

a rotary evaporator followed by a mechanical pump (0.05 torr) upon cooling to room

temperature. A red-brown solid (73.0 mg, mp 230 °C with decomposition) in an 84% yield

was produced and it was stored in a glovebox. 1H NMR (500 MHz, CD3CN) δ 9.15 (s, 2H),

8.86 (d, J = 8.2 Hz, 2H), 8.67 (d, J = 5.9 Hz, 2H), 8.33 (s, 2H), 8.11 (dd, J = 8.1 and 6.2

Hz, 2H), 8.07 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.1 Hz, 2H), 7.41 (t, J = 7.1 Hz, 2H), 7.11 (d,

J = 8.4 Hz, 2H), 7.00 (s, 2H), 4.42 (s, 6H). 13C NMR (125 MHz, CD3CN) δ 151.6, 146.7,

146.2, 144.4, 139.7, 135.9, 133.5, 130.3, 129.9, 129.5, 128.4, 125.7, 125.1, 124.9, 115.1,


C32H26N2O2 (M – 2I-)2+ 235.0992, found 235.0994.

(R)-3,3′-Di(3-pyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl chloride (6.20). In a 6-dram

vial, (R)-3,3′-di(3-pyridyl)-2,2′-dihydroxyl-1,1′-binaphthyl 6.9 (49.5 mg, 0.112 mmol) was

suspended in 3 mL of methanol. Concentrated HCl (1 mL) was then added dropwise over

2 min and the mixture was stirred for 30 min, resulting in a homogenous, light-yellow

156

solution. The reaction was then triturated into 15 mL of anhydrous diethyl ether and the

supernatant was removed by syringe. The white precipitate was washed with additional

diethyl ether (2 x 15 mL) and hexanes (1 x 15 mL) before it was dried with a rotary

evaporator followed by mechanical pump (0.05 torr) to afford 46.5 mg (81%) of a yellow

solid (mp 230-235 °C). 1H NMR (400 MHz, d6-DMSO) δ 9.22 (s, 2H), 9.06 (bs, 2H), 8.94

(d, J = 5.5 Hz, 2H), 8.90 (d, J = 8.1 Hz, 2H), 8.29 (s, 2H), 8.18 (dd, J = 8.2, 5.6 Hz, 2H),

8.02 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.0 Hz, 2H), 6.96 (d, J = 8.4

Hz, 2H), missing N-H signals due to broadening. 13C NMR (100 MHz, d6-DMSO) δ 150.8,

145.7, 142.0, 140.1, 137.5, 134.5, 131.4, 128.7, 128.5, 127.5, 126.8, 125.3, 124.2, 123.7,


C30H21N2O2 (M – H+ – 2Cl-)+ 441.1598, found 441.1595, and calcd for C30H22N2O2

(M – 2Cl-

)2+ 221.0835, found 221.0854.

General Protonation Procedure with Trifluoromethanesulfimide.

In a 6-dram vial, trifluoromethanesulfimide (68.0 mg, 0.242 mmol) and a stir bar were

added and the atmosphere was purged with argon. In a separate vial, the corresponding

3,3′-dipyridyl-2,2′-dihydroxyl-1,1′-binaphthyl was dissolved in dichloromethane and this

solution was added dropwise over 1 min to the trifluoromethanesulfimide and then stirred

for 30 min. Pentane (15 mL) was subsequently added, resulting in the formation of a

precipitate. The supernatant was removed by syringe and the solid residue was washed

with additional pentane (15 mL). Removal of the supernatant was repeated and the

sample was dried with a rotary evaporator followed by a mechanical pump (0.01 torr).

(R)-3,3′-Di(3-pyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl

bis(trifluoromethanesulfonyl)imide (6.22). Following the general procedure

trifluoromethanesulfimide (68.0 mg, 0.242 mmol) and (R)-3,3′-di(3-pyridyl)-2,2′-dihydroxyl-

157

1,1′-binaphthyl 6.9 (50.0 mg, 0.114 mmol) in 1.5 mL of dichloromethane afforded 103.3

mg (91%) of a shiny, colorless solid (mp 55-59 °C). 1H NMR (400 MHz, CD2Cl2) δ 14.08

(s, 2H), 9.23 (dd, J = 6.9, 1.8 Hz, 2H), 8.96 (dt, J = 8.3, 1.5 Hz, 2H), 8.72 (t, J = 6.2 Hz,

2H), 8.25 (s, 2H), 8.15 (ddd, J = 7.9, 6.3, 1.0 Hz, 2H), 8.08 (d, J = 7.9 Hz, 2H), 7.55 (ddd,

J = 8.2, 7.0, 1.3 Hz, 2H), 7.48 (ddd, J = 8.2, 7.0, 1.3 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 5.68

(s, 2H). 13C NMR (100 MHz, CD2Cl2) δ 149.8, 147.9, 142.3, 139.6, 138.9, 134.6, 133.6,

130.0, 129.9, 129.7, 127.8, 126.1, 124.4, 122.8, 120.0 (q, 1JF-C = 321 Hz), 115.2. 19F NMR

(376 MHz, CD2Cl2) δ -79.1. IR (ATR source) 3446, 3253, 3139, 3099, 1622, 1600, 1551,

1504, 1346, 1182, 1126 cm-1. HRMS-ESI: calcd for C30H22N2O2 (M – 2(C2F6NO4S2)-)2+

441.1598, found 441.1578 and calcd for C30H21N2O2 (M – 2(C2F6NO4S2)- – H+)+ 221.0835,

found 221.0843.

(R)-3,3′-Di(2-pyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl

bis(trifluoromethanesulfonyl)imide (6.23). Following the general procedure

trifluoromethanesulfimide (75.5 mg, 0.269 mmol) and (R)-3,3′-di(2-pyridyl)-2,2′-dihydroxyl-

1,1′-binaphthyl 6.10 (59.0 mg, 0.134 mmol) in 2.0 mL of dichloromethane afforded 125.0

mg (93%) of a shiny, yellow solid (mp 66-69 °C). 1H NMR (500 MHz, CD2Cl2) δ 14.05 (s,

2H), 8.73 – 8.65 (m, 4H), 8.62 (s, 2H), 8.60 – 8.55 (m, 2H), 8.15 (d, J = 8.1 Hz, 2H), 7.97

(dd, J = 7.6 and 6.1 Hz, 2H), 7.58 (ddd, J = 7.6, 6.9, 1.2 Hz, 2H), 7.52 (ddd, J = 7.6, 6.9,

1.2 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.85 (s, 2H).13C NMR (100 MHz, CD2Cl2) δ 150.9,

149.5, 147.6, 140.8, 136.0, 135.1, 131.3, 130.5, 129.7, 127.4, 126.6, 125.8, 124.7, 119.9

(q, 1JF-C = 321 Hz), 118.7, 113.5. 19F NMR (470 MHz, CD2Cl2) δ -79.1. IR (ATR source)

3402, 3263, 3115, 1620, 1605, 1542, 1503, 1346, 1180, 1124 cm-1. HRMS-ESI: calcd for

C30H22N2O2 (M – 2(C2F6NO4S2)-)2+ 441.1598, found 441.1591 and calcd for C30H21N2O2 (M

– 2(C2F6NO4S2)- – H+)+ 221.0835, found 221.0842.

158

General Anion-Exchange Procedure.

Under inert atmosphere, sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate and the

corresponding iodide salt were stirred in CH2Cl2 overnight, resulting in a colorless solution

and white precipitate. The reaction mixture was filtered through a 0.45 µm PTFE syringe

filter which was washed with additional CH2Cl2. The solvent was removed with a rotary

evaporator and the remaining solid residue was dissolved in CH2Cl2 and the filtration

process was repeated. Concentration under reduced pressure afforded the product, which

was further dried with a mechanical pump (0.05 torr) and then stored in a glovebox.

(R)-3,3′-Di(3-N-octylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl tetrakis[3,5-

bis(trifluoromethyl)phenyl]borate (6.15). Following the general procedure, sodium

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (202 mg, 0.228 mmol) and (R)-3,3′-di(3-N-

octylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl iodide 6.13 (98.9 mg, 0.107 mmol) in 7 mL

of CH2Cl2 afforded 243 mg (95%) of a colorless, fluffy solid (mp 52-55 °C). 1H NMR (400

MHz, CD2Cl2) δ 8.94 (s, 2H), 8.83 (dt, J = 8.3, 1.5 Hz, 2H), 8.44 (d, J = 6.1 Hz, 2H), 8.23

(s, 2H), 8.06 (dd, J = 8.3, 6.0 Hz, 4H), 7.70 (s, 16H), 7.60 – 7.46 (m, 12H), 7.22 (d, J = 8.3

Hz, 2H), 5.51 (s, 2H), 4.53 (t, J = 7.6 Hz, 4H), 2.11 – 1.99 (m, 4H), 1.46 – 1.03 (m, 20H),

0.83 (t, J = 6.8 Hz, 6H).13C NMR (125 MHz, CD2Cl2) δ 162.1 (q, 1JB-C = 49.8 Hz), 149.3,

146.6, 144.0, 141.5, 140.2, 135.2, 134.6, 134.0, 130.7, 129.93, 129.87, 129.6 (qq, 3JB-C =

2.9 Hz and 2JF-C = 31.6 Hz), 129.0, 126.8, 125.0 (q, 1JF-C = 273 Hz), 124.2, 121.7, 117.9

(sept, 3JF-C = 4.1 Hz),8 112.5, 64.0, 32.0, 31.9, 29.2, 29.1, 26.4, 22.9, 14.1. 19F NMR (376

MHz, CD2Cl2) δ -62.7. IR (ATR source) 3540, 1609, 1504, 1353, 1272, 1112 cm-1. HRMS-

ESI: calcd for C46H54N2O2 (M – 2(C32H12BF24)-)2+ 333.2087, found 333.2076.

(R)-3,3′-Di(3-N-methylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl tetrakis[3,5-

bis(trifluoromethyl)phenyl]borate (6.16). Following the general procedure, sodium

159

tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (130 mg, 0.147 mmol) and (R)-3,3′-di(3-N-

methylpyridinium)-2,2′-dihydroxyl-1,1′-binaphthyl iodide 6.14 (50.4 mg, 0.0696 mmol) in 4

mL of CH2Cl2 afforded 149 mg (97%) of a colorless solid (mp 75-77 °C). 1H NMR (500

MHz, CD2Cl2) δ 8.93 (s, 2H), 8.85 (d, J = 8.3 Hz, 2H), 8.39 (d, J = 6.1 Hz, 2H), 8.22 (s,

2H), 8.14 – 8.00 (m, 4H), 7.71 (s, 16H), 7.57 – 7.54 (m, 10H), 7.50 (dt, J = 7.3, 1.2 Hz,

2H), 7.22 (d, J = 8.3 Hz, 2H), 5.52 (s, 2H), 4.38 (s, 6H). 13C NMR (125 MHz, CD2Cl2) δ

162.1 (q, 1JB-C = 49.8 Hz), 149.3, 146.6, 144.9, 142.4, 140.3, 135.2, 134.6, 134.0, 130.8,

129.93, 129.90, 129.3 (qq, 3JB-C = 2.9 Hz and 2JF-C = 31.8 Hz), 129.0, 126.8, 125.0 (q, 1JF-

C = 273 Hz), 124.2, 121.6, 117.9 (sept, 3JF-C = 4.5),8 112.5, 49.7. 19F NMR (376 MHz,

CD2Cl2) δ -62.7. IR (ATR source) 3542, 1609, 1506, 1354, 1272, 1110 cm-1. HRMS-ESI:

calcd for C32H26N2O2 (M – 2(C32H12BF24)-)2+ 235.0992, found 235.0994.

160

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As Useful Measure for Comparison of Chiral Catalysts, Demonstrated On Asymmetric

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retention time of the second peak by the retention time of the first. Therefore, α ≥ 1.

(26) This parameter takes the retention times and peak widths into account. More details

are provided in the appendix.

(27) A similar concern for reporting chromatographic errors has been expressed before.

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185

(28) The given percentages correspond to the valley height between the two enantiomers

above the baseline relative to the height of the top of the signal for the first enantiomer. A

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(29) The respective separation factors (α) and resolutions (Rs) for our data are as follows:

1.66 and 2.37 (1% overlap), 1.60 and 1.76 (4% overlap), and 1.36 and 1.33 (17% overlap).

(30) A survey of the Supporting Information in the first two issues of J. Org. Chem. in 2018

and the first three issues of Org. Biomol. Chem. in 2019 provided copies of 351 racemic

HPLC chromatograms used to determine enantioselectivities. Of these, 196

chromatograms (56%) had better resolutions than those reported in this work, 103 (29%)

were similar to the 1% overlap separations, 40 (11%) had ~2–10% overlap, and 12 (4%)

were similar or worse than our 17% overlap data.

(31) Enantiomer excess measurements using UV-vis and circular dichroism of overlapping

HPLC peaks has been reported. See: Holik, M.; Mannschreck, A. Determining

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Methods. Chemom. Intell. Lab. Syst. 2004, 72, 153-160.

(32) Value provided by Sigma-Aldrich.

(33) See the appendix for details.

(34) Dyson, N. Chromatographic Integration Methods; 2nd Ed., Royal Society of

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(35) For comparison of the vertical drop method versus tangent skimming, see: refs. 17

and 18.

(36) See the appendix for more details on all post-analysis software parameters.

(37) If the slope sensitivity (alternately called the peak threshold) is set to too large a value,

the peak integration starts later and ends earlier and this can lead to small components

being reduced in intensity or missed altogether. Alternatively, if this parameter is made too

small, the integration start point begins earlier and ends later leading to several potential

186

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(38) The effect of a different slope sensitivity parameter on the ee determination is given

in the appendix. In general, variability in the determined ee increases when the signals for

the enantiomers in the chromatogram overlap and/or signal to noise (S/N) issues are

present. If the chromatography is excellent (i.e. no peak overlap and good S/N), this

parameter has much less impact on the observed ee values.

(39) Due to the difference in the peak heights of the enantiomers in the HPLC

chromatogram of a racemic sample (see Figure 3.1), different slope sensitivity ranges

were observed. See the appendix for additional details.

(40) We found that a value of 0.10 at 254 nm is satisfactory when the absorbance for the

major enantiomer is between 20 and 2000 mAU at λmin and λmax, respectively. Larger

absorbances need to be avoided as they typically are out of the linear range of the UV-vis

detector and smaller values lead to dynamic range issues (i.e., the minor enantiomer is

too small to accurately determine).

(41) See the appendix for all tabulated data collected at individual wavelengths.

(42) There are 10 combinations of three values from five measurements and they were all

computed (see appendix). The uncertainty ranges span up to an order of magnitude and

the largest values, which were used in Figure 3.3, most often correspond to the mode.

(43) Baseline separation is the best way to ensure reliable data collection via HPLC

regardless of elution order (see refs. 17-24), however, this can be difficult to accomplish.

(44) Variation in the values for the slope sensitivity and peak width parameters were

explored but did not lead to detection of the minor component.

(45) Pretsch, E.; Buhlmann, P.; Affolter, C. Structure Determination of Organic

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420.

187

(46) For an extreme case of molar absorptivity dependence on the monitored wavelength,

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(47) See the appendix for plots regarding α and Rs as well as the measurement accuracies

and uncertainties.

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201

Appendices

Appendix for Chapter 2

Figure S1. HCl gas generation setup.

Table S1. Computed B3LYP/6-31G(2df,p) and Experimentally Observed O–H and N–

H Vibrational Frequencies for the Indicated Acidsa

cmpd calcb expt

2.2Me 3792

2.3Me 3799 3513

2.4Me 3778 3480

PhOH 3822 3582

4-NO2PhOH 3816 3559

2.2H 3789

2.3H 3797 3516

2.4H 3772 3477

2.5H 3563* 3307

2.2H 3554* 3316

2.3H 3564* 3308

2.4H 3590* 3348 aAll vibrational frequencies are in cm–1. bUnscaled O–H and N–H stretching frequencies, where the latter

values are indicated with a star.

A

B

C

G

D

E

F

202

Figure S2. Observed vs. computed vibrational frequencies for the free acids. A linear least

squares fit of the data affords Experimental frequency (cm–1) = 0.896 × calc freq. (cm–1) +

121.9, r2 = 0.968.

Table S2. Computed B3LYP/6-31G(2df,p) and Experimentally Observed O–H and

N–H Vibrational Frequencies for the Indicated Acids in the Presence of

Acetonitrilea

cmpd calcb expt

2.2Me 2984 2977

2.3Me 3215 3179

2.4Me 3134 3082

PhOH 3658 3412

4-NO2PhOH 3576 3330

2.2H 3109c 3071

2.3H 3283c 3193

2.4H 3210c 3249

2.5H 2955* 2903

2.2H 2945* 2962

2.3H 2957* 2902

2.4H 3175*c 3107

aAll vibrational frequencies are in cm–1. bUnscaled O–H and N–H stretching frequencies, where the

latter values are indicated with a star. cCalculated with both the O–H and N–H groups complexed

to a molecule of acetonitrile.

3200

3250

3300

3350

3400

3450

3500

3550

3600

3650

3700

3500 3550 3600 3650 3700 3750 3800 3850 3900

Ob

serv

ed F

req

uen

cy (

cm–

1 )

Calculated Frequency (cm–1)

203

Figure S3. Observed vs. computed vibrational frequencies for the acid/CD3CN

complexes. A linear least squares fit of the data affords experimental frequency (cm–1) =

0.669 × calc freq. (cm–1) + 972.4, r2 = 0.962; open circle is for 2.4H, which was omitted

from the regression analysis.

2800

2900

3000

3100

3200

3300

3400

3500

2800 2900 3000 3100 3200 3300 3400 3500 3600 3700 3800 3900

Ob

serv

ed F

req

uen

cy (

cm–1

)

Calculated Frequency (cm–1)

204

Table S3. Kinetic Data for the Friedel-Crafts Reaction of N-Methylindole (50 mM)

with trans-β-Nitrostyrene (500 mM) in CD2Cl2 at 27 °C

cat. (10 mol%, 5 mM) Trial 1 Trial 2

Time (min) Conv. (%) Time (min) Conv. (%)

2.3Me

55.3 115.4 174.8 234.4 295.0 354.9 415.7 477.5 534.6 597.2 656.2 715.4 1443.3 1513.1 1570.3

8.3 16.4 23.5 29.9 36.2 41.4 46.4 51.5 54.7 58.3 61.6 64.5 87.2 88.6 89.3

47.3 107.5 168.3 229.0 288.4 348.9 410.7 469.1 533.6 1430.2 1489.4 1548.4

6.8 15.3 22.7 29.4 35.1 40.8 45.7 49.8 54.1 86.2 87.2 87.9

2.4Me

27.3 58.3 117.3 181.6 235.9 297.4 364.3 417.1 481.2 537.9 603.8

6.3 13.5 26.1 37.9 46.4 54.2 61.0 66.3 71.1 75.5 79.3

54.0 115.4 176.2 233.5 294.2 354.3 416.1 482.5 534.5

14.0 28.9 40.2 49.6 58.3 64.6 70.7 76.5 79.0

2.2Me

25.3 54.1 112.4 146.0 171.3 214.0 252.1 312.2

11.8 25.0 45.2 52.9 59.0 66.3 71.8 77.4

48.6 89.2 129.2 169.3 208.1 253.5 292.7 329.9

18.3 32.0 42.6 51.7 59.2 65.8 70.7 75.3

2.5H

32.7 70.6 91.7 123.4 156.3 187.3 215.3 286.0 329.1 360.7 391.2 422.0

14.5 28.1 34.9 44.0 50.6 57.3 62.0 72.8 77.6 80.1 82.1 84.2

31.7 61.3 90.8 117.4 179.7 210.5 240.8 271.1 301.9 332.2 360.9

13.8 24.6 33.6 40.7 54.5 60.0 64.8 68.6 72.5 75.8 78.2

205

2.3H

39.3 72.3 102.7 141.8 176.4 209.2 237.1 273.2 308.0 337.7 367.4 395.6 420.6

16.4 27.9 36.7 47.0 53.6 59.3 63.7 68.0 72.2 75.2 78.2 80.4 82.2

27.1 57.8 89.9 119.4 148.6 179.3 239.1 272.9 300.7 340.2 378.2 420.3 448.7

11.0 21.7 31.5 38.9 46.0 52.5 61.9 67.2 69.6 73.4 77.0 80.9 82.4

2.4H

42.9 69.3 101.9 131.0 189.7 253.9 310.8 373.7 418.5 478.9 535.8

12.0 18.9 27.0 33.6 44.4 55.0 62.0 69.2 72.9 77.5 80.8

65.7 114.0 176.5 235.6 297.3 362.6 416.2 462.9

17.8 29.2 41.3 51.3 59.4 66.1 71.6 74.9

2.2H

3.6 9.9 14.3 19.1 24.2 29.2 34.3 39.6 44.7 49.5 54.4 59.5 64.8 69.6 74.9 79.8 85.1

10.4 24.2 32.9 40.8 47.6 53.6 58.4 63.3 67.5 70.9 73.8 76.7 79.3 81.3 83.4 85.1 86.7

6.5 10.8 15.8 21.1 26.5 31.2 36.2 41.2 46.4 51.5 56.5 61.6 66.6 71.7 76.7 82.4

18.9 29.7 39.3 47.6 55.1 60.3 65.0 69.5 73.1 76.2 79.1 81.4 83.6 85.7 87.6 88.9

2.6

44.4 86.7 133.5 199.1 254.1 343.4 402.0 460.7 521.2 580.7 672.0

8.0 16.2 23.3 33.8 40.1 50.1 55.4 59.9 64.2 68.5 73.3

59.3 120.4 178.7 238.8 298.9 360.8 420.0 479.9 540.0 603.1 660.5 720.6

12.0 22.5 30.6 38.9 45.5 51.5 56.5 60.8 65.1 68.8 72.2 75.3

206

2.5Mea

1144.6 2600.5 4043.4 5666.6 8679.3 9859.8 11237.6 12652.0 14072.0

5.4 (5.0) 8.8 (8.0)

11.8 (10.5) 14.5 (12.8) 19.4 (16.7) 21.3 (18.2) 23.5 (20.0) 25.6 (21.7) 28.2 (24.0)

1455.6 2900.2 4522.1 7534.8 8714.7 10093.5 11537.4 12957.8

6.2 (5.8) 9.1 (8.2)

12.0 (10.6) 16.0 (13.7) 17.8 (15.1) 19.6 (16.5) 21.5 (18.0) 23.1 (19.1)

None/Background

2943.9 12850.4 22945.5 33097.5

1.0 3.8 6.5 9.9

aValues in parentheses were corrected for the background reaction.

Figure S4. Pseudo-first-order fitting of the Friedel-Crafts reaction of N-methylindole with

trans-β-nitrostyrene catalyzed by the methylated hydroxypyridines. Results for 2.2Me,

2.3Me, and 2.4Me are represented by triangles, circles, and squares, respectively. Filled

symbols are for the first data set and open ones are the second run.

y = -0.00145x - 0.0126R² = 0.9993

y = -0.00261x + 0.00177R² = 0.9997

y = -0.00296x + 0.00348R² = 0.9996

y = -0.00146x - 0.00675R² = 0.9996

y = -0.00486x - 0.0266R² = 0.9965

y = -0.00423x - 0.00449R² = 0.9997

-2.00

-1.80

-1.60

-1.40

-1.20

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0 100 200 300 400 500 600 700 800

ln(M

I)

Time (min)

207


trans-β-nitrostyrene catalyzed by 2.5H and 2.6, which are represented by circles and

squares, respectively. Filled symbols are for the first data set and open ones are the

second run.


trans-β-nitrostyrene catalyzed by the protonated hydroxypyridines. Results for 2.2H,

2.3H, and 2.4H are represented by triangles, circles, and squares, respectively. Filled

symbols are for the first data set and open ones are the second run.

y = -0.00440x - 0.0210R² = 0.9992

y = -0.00421x - 0.0204R² = 0.9996

y = -0.00197x - 0.00619R² = 0.9996

y = -0.00191x - 0.0208R² = 0.9995

-2.00

-1.80

-1.60

-1.40

-1.20

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0 100 200 300 400 500 600 700 800

ln (

MI)

Time (min)

y = -0.0234x - 0.0572R² = 0.9986

y = -0.00406x - 0.0335R² = 0.9992

y = -0.0263x - 0.0721R² = 0.9981

y = -0.00386x - 0.0272R² = 0.9990

y = -0.00311x + 0.00024R² = 0.9998

y = -0.00300x - 0.00309R² = 0.9998

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

0 100 200 300 400 500 600

ln (

MI)

Time (min)

208

Table S4. Dimer Determination Data

2.3Me

[2.3Me]

(M)

Observed δ (ppm) Calculated δ (ppm)

O-H CH3 O-H CH,3

3.85E-03 7.853 4.306 7.865 4.305

3.08E-03 7.793 4.310 7.776 4.310

1.93E-03 7.602 4.320 7.598 4.322

1.28E-03 7.449 4.331 7.460 4.331

1.03E-03 7.397 4.335 7.392 4.335

7.71E-04 7.301 4.341 7.315 4.340

6.16E-04 7.274 4.344 7.262 4.344

2.3H

[2.3H] (M) Observed δ (ppm) Calculated δ (ppm)

Ha Hb Ha Hb

4.38E-03 8.252 8.222 8.251 8.221

3.13E-03 8.262 8.234 8.263 8.236

2.43E-03 8.273 8.246 8.272 8.247

1.82E-03 8.284 8.260 8.283 8.260

1.46E-03 8.292 8.270 8.292 8.270

1.09E-03 8.302 8.284 8.302 8.283

8.76E-04 8.310 8.292 8.310 8.293

2.4H


N-H O-H N-H O-H

6.02E-03 11.012 9.383 11.019 9.398

5.42E-03 11.021 9.391 11.017 9.379

4.17E-03 11.012 9.338 11.009 9.326

3.01E-03 11.004 9.249 10.999 9.252

2.36E-03 10.981 9.167 10.990 9.191

2.08E-03 10.989 9.177 10.985 9.159

Trial 1

209


N-H Ha N-H Ha

3.13E-03 11.101 8.328 11.107 8.328

2.78E-03 11.097 8.333 11.097 8.332

2.50E-03 11.095 8.335 11.088 8.336

1.92E-03 11.070 8.346 11.065 8.345

1.39E-03 11.025 8.357 11.034 8.358

1.09E-03 11.009 8.368 11.011 8.367

9.62E-04 11.004 8.372 10.999 8.372

2.6

[2.6] (M) Observed δ (ppm) Calculated δ (ppm)

CH3 Ha CH3 Ha

3.12E-02 4.205 8.459 4.205 8.459

2.08E-02 4.215 8.472 4.215 8.472

1.56E-02 4.221 8.480 4.222 8.480

1.25E-02 4.226 8.487 4.226 8.486

1.04E-02 4.230 8.491 4.230 8.491

8.92E-03 4.233 8.495 4.234 8.496

7.81E-03 4.236 8.499 4.236 8.499

6.94E-03 4.238 8.502 4.238 8.502

6.25E-03 4.240 8.504 4.240 8.504

Color Changes in the UV-vis Titrations

The sensor (solution A, 2.1) and titrant (solution B, e.g., 2.1 + 2.3H) solutions were red

and typically yellow, respectively (Figure S5). In this case, the titration solution starts off

as red and transitions to yellow as the process proceeds. For 2.2Me and 2.2H, the titrant

solution was light red-purple (i.e. 2.1 + 2.2Me or 2.2H). As a result, these titrations went

from red to yellow and then to the light red-purple color as shown in Figure S6.

Trial 2

210

Figure S7. Colored solutions containing only the sensor (2.1), the sensor and 2.3H (2.1 +

2.3H), and the sensor and 2.2Me (2.1 + 2.2Me).

Figure S8. Color changes during the course of the titration when increased amounts of

2.2Me were added.

2.1 2.1 + 2.2Me 2.1 + 2.3H

0.00 equiv. 0.46 equiv. 1.52 equiv. 5.33 equiv. 8.29 equiv. 15.99 equiv.

211

Representative Titration Plots and the Corresponding UV-vis Spectra

Figure S9. Titration curve of 2.2Me and the corresponding UV-vis spectra from 300-600 nm.

405.0

425.0

445.0

465.0

485.0

505.0

0.0 5.0 10.0 15.0 20.0 25.0

λ max

(nm

)

Equivalents of 2.2Me

0.00

0.10

0.20

0.30

0.40

0.50

0.60

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.22 equiv.

0.33 equiv.

0.44 equiv.

0.55 equiv.

0.65 equiv.

0.76 equiv.

0.86 equiv.

0.96 equiv.

1.07 equiv.

1.46 equiv.

1.94 equiv.

2.49 equiv.

3.33 equiv.

5.80 equiv.

8.81 equiv.

11.19 equiv.

212


465.0

470.0

475.0

480.0

485.0

490.0

495.0

500.0

505.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0

λ max

(nm

)


0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0 equiv.

0.25 equiv.

0.49 equiv.

0.73 equiv.

0.96 equiv.

1.19 equiv.

1.74 equiv.

2.27 equiv.

2.77 equiv.

3.25 equiv.

4.15 equiv.

5.75 equiv.

7.12 equiv.

9.35 equiv.

11.08 equiv.

12.46 equiv.

213

Figure S11. Titration curve of 2.4Me and the corresponding UV-vis spectra from 300-600

nm.

460.0

465.0

470.0

475.0

480.0

485.0

490.0

495.0

500.0

505.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0

λ max

(nm

)


0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

300.0 350.0 400.0 450.0 500.0 550.0 600.0 650.0

Ab

sorb

acn

e (A

)

Wavelength (nm)

0.00 equiv.

0.27 equiv.

0.54 equiv.

0.81 equiv.

1.07 equiv.

1.32 equiv.

1.94 equiv.

2.52 equiv.

3.62 equiv.

5.55 equiv.

7.93 equiv.

10.94 equiv.

13.15 equiv.

214


470.0

475.0

480.0

485.0

490.0

495.0

500.0

505.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

λ max

(nm

)


0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

10.80equiv.20.61equiv.29.57equiv.37.79equiv.45.35equiv.58.78equiv.

215

Figure S13. Titration curve of 2.5H and the corresponding UV-vis spectra from 300-600 nm.

465.0

470.0

475.0

480.0

485.0

490.0

495.0

500.0

505.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

λ max

(nm

)

Equivalents of 2.5H

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.46 equiv.

0.91 equiv.

1.35 equiv.

1.91 equiv.

2.84 equiv.

4.08 equiv.

6.25 equiv.

8.10 equiv.

216


400.0

420.0

440.0

460.0

480.0

500.0

0.0 5.0 10.0 15.0 20.0 25.0 30.0

λ max

(nm

)

Equivalents of 2.2H

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.13 equiv.

0.25 equiv.

0.37 equiv.

0.50 equiv.

0.74 equiv.

0.97 equiv.

1.54 equiv.

2.09 equiv.

3.11 equiv.

4.04 equiv.

5.84 equiv.

7.22 equiv.

8.43 equiv.

10.84 equiv.

12.64 equiv.

25.29 equiv.

217


465.0

470.0

475.0

480.0

485.0

490.0

495.0

500.0

505.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

λ max

(nm

)

Equivalents of 2.3H

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.17 equiv.

0.35 equiv.

0.52 equiv.

0.69 equiv.

0.85 equiv.

1.02 equiv.

1.35 equiv.

1.67 equiv.

2.14 equiv.

2.89 equiv.

4.30 equiv.

5.59 equiv.

7.87 equiv.

10.70 equiv.

218


445.0

455.0

465.0

475.0

485.0

495.0

505.0

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

λ max

(nm

)

Equivalents of 2.4H

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.16 equiv.

0.31 equiv.

0.47 equiv.

0.77 equiv.

1.07 equiv.

1.50 equiv.

2.20 equiv.

2.87 equiv.

4.12 equiv.

5.27 equiv.

7.29 equiv.

10.53 equiv.

13.54 equiv.

15.80 equiv.

31.59 equiv.

219

Figure S17. Titration curve of 2.6 and the corresponding UV-vis spectra from 300-600

nm.

435.0

445.0

455.0

465.0

475.0

485.0

495.0

505.0

0.0 5.0 10.0 15.0 20.0 25.0

λ max

(nm

)

Equivalents of 2.6

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

300.0 350.0 400.0 450.0 500.0 550.0 600.0

Ab

sorb

ance

(A

)

Wavelength (nm)

0.00 equiv.

0.21 equiv.

0.41 equiv.

0.61 equiv.

0.81 equiv.

1.01 equiv.

1.40 equiv.

1.97 equiv.

2.88 equiv.

3.75 equiv.

5.39 equiv.

6.88 equiv.

9.53 equiv.

11.80 equiv.

13.77 equiv.

17.70 equiv.

20.65 equiv.

220

Data Uploaded to BindFit and the Corresponding Fits

Table S5. Observed UV-vis Data and the Corresponding Nonlinear Fits for 2.2Me.

[2.1] (M) [2.2Me]

(M)

Observed Absorbance Calculated Absorbancea

400 nm 430 nm 500 nm 530 nm 400 nm 430 nm 500 nm 530 nm

2.66E-05 0 0.0468 0.1273 0.4467 0.3295 0.0468 0.1273 0.4467 0.3295

2.66E-05 2.96E-06 0.0647 0.1556 0.4270 0.3059 0.0754 0.1751 0.4007 0.2870

2.66E-05 5.90E-06 0.0964 0.1989 0.3835 0.2658 0.1014 0.2159 0.3606 0.2506

2.66E-05 8.81E-06 0.1261 0.2388 0.3380 0.2264 0.1250 0.2507 0.3256 0.2194

2.66E-05 1.17E-05 0.1519 0.2720 0.2992 0.1942 0.1463 0.2802 0.2951 0.1927

2.66E-05 1.45E-05 0.1757 0.3021 0.2653 0.1659 0.1657 0.3053 0.2684 0.1700

2.66E-05 1.74E-05 0.1952 0.3275 0.2398 0.1439 0.1833 0.3265 0.2451 0.1505

2.66E-05 2.02E-05 0.2125 0.3484 0.2193 0.1285 0.1994 0.3444 0.2248 0.1340

2.66E-05 2.29E-05 0.2234 0.3601 0.1965 0.1119 0.2140 0.3596 0.2070 0.1198

2.66E-05 2.57E-05 0.2357 0.3739 0.1820 0.1007 0.2273 0.3723 0.1913 0.1078

2.66E-05 2.84E-05 0.2462 0.3847 0.1683 0.0904 0.2395 0.3831 0.1776 0.0976

2.66E-05 3.90E-05 0.2756 0.4105 0.1336 0.0685 0.2789 0.4111 0.1373 0.0699

2.66E-05 5.17E-05 0.3041 0.4297 0.1112 0.0574 0.3134 0.4261 0.1079 0.0535

2.66E-05 6.62E-05 0.3249 0.4344 0.0930 0.0513 0.3414 0.4306 0.0887 0.0465

2.66E-05 8.87E-05 0.3517 0.4332 0.0800 0.0516 0.3704 0.4265 0.0740 0.0463

2.66E-05 1.19E-04 0.3796 0.4241 0.0720 0.0583 0.3945 0.4153 0.0666 0.0525

2.66E-05 1.54E-04 0.4039 0.4087 0.0687 0.0657 0.4115 0.4023 0.0645 0.0610

2.66E-05 1.99E-04 0.4243 0.3887 0.0680 0.0736 0.4246 0.3890 0.0648 0.0702

2.66E-05 2.35E-04 0.4369 0.3770 0.0671 0.0789 0.4317 0.3805 0.0658 0.0763

2.66E-05 2.65E-04 0.4449 0.3683 0.0673 0.0820 0.4362 0.3746 0.0668 0.0806

2.66E-05 2.98E-04 0.4496 0.3605 0.0664 0.0840 0.4401 0.3691 0.0678 0.0846

2.66E-05 5.96E-04 0.4651 0.3438 0.0635 0.0887 0.4556 0.3439 0.0739 0.1032 aObtained from the 2:1 binding model in the BindFit program.

221

[2.1] (M) [2.2Me]

(M)



2.44E-05 0 0.0295 0.1011 0.3851 0.2834 0.0295 0.1011 0.3851 0.2834

2.44E-05 3.88E-06 0.0646 0.1497 0.3360 0.2377 0.0669 0.1659 0.3212 0.2254

2.44E-05 7.73E-06 0.1045 0.2054 0.2771 0.1853 0.0989 0.2151 0.2710 0.1809

2.44E-05 1.15E-05 0.1368 0.2475 0.2332 0.1478 0.1262 0.2521 0.2314 0.1470

2.44E-05 1.53E-05 0.1608 0.2793 0.1954 0.1159 0.1496 0.2801 0.2000 0.1211

2.44E-05 1.90E-05 0.1796 0.2998 0.1688 0.0960 0.1699 0.3011 0.1750 0.1013

2.44E-05 2.64E-05 0.2081 0.3325 0.1342 0.0696 0.2028 0.3290 0.1386 0.0742

2.44E-05 3.72E-05 0.2349 0.3539 0.1030 0.0500 0.2389 0.3499 0.1053 0.0526

2.44E-05 5.45E-05 0.2660 0.3676 0.0795 0.0402 0.2782 0.3601 0.0776 0.0392

2.44E-05 7.10E-05 0.2895 0.3702 0.0689 0.0407 0.3033 0.3594 0.0648 0.0367

2.44E-05 1.30E-04 0.3391 0.3439 0.0537 0.0495 0.3505 0.3416 0.0519 0.0455

2.44E-05 2.02E-04 0.3747 0.3134 0.0524 0.0623 0.3754 0.3230 0.0513 0.0577

2.44E-05 2.60E-04 0.3879 0.3019 0.0533 0.0676 0.3864 0.3127 0.0525 0.0648

2.44E-05 3.35E-04 0.3987 0.2945 0.0532 0.0711 0.3953 0.3034 0.0541 0.0713

2.44E-05 3.90E-04 0.4049 0.2925 0.0544 0.0739 0.4000 0.2982 0.0552 0.0750


222


[2.1] (M) [2.3Me]

(M)


441 nm 471nm 500 nm 530 nm 441 nm 471 nm 500 nm 530 nm

2.89E-05 0 0.1484 0.2975 0.3761 0.2731 0.1484 0.2975 0.3761 0.2731

2.89E-05 7.12E-06 0.1655 0.3095 0.3722 0.2574 0.1647 0.3081 0.3673 0.2511

2.89E-05 1.41E-05 0.1791 0.3197 0.3649 0.2385 0.1788 0.3174 0.3598 0.2321

2.89E-05 2.09E-05 0.1926 0.3289 0.3604 0.2225 0.1911 0.3254 0.3532 0.2155

2.89E-05 2.77E-05 0.2017 0.3331 0.3513 0.2048 0.2018 0.3323 0.3475 0.2010

2.89E-05 3.42E-05 0.2137 0.3431 0.3492 0.1935 0.2111 0.3384 0.3424 0.1884

2.89E-05 5.02E-05 0.2323 0.3546 0.3375 0.1667 0.2298 0.3506 0.3325 0.1632

2.89E-05 6.54E-05 0.2462 0.3627 0.3287 0.1464 0.2435 0.3595 0.3251 0.1447

2.89E-05 7.99E-05 0.2579 0.3709 0.3236 0.1320 0.2539 0.3662 0.3196 0.1308

2.89E-05 9.38E-05 0.2675 0.3767 0.3190 0.1196 0.2619 0.3715 0.3153 0.1199

2.89E-05 1.20E-04 0.2774 0.3821 0.3100 0.1020 0.2735 0.3790 0.3091 0.1043

2.89E-05 1.66E-04 0.2907 0.3908 0.3010 0.0823 0.2870 0.3878 0.3018 0.0860

2.89E-05 2.05E-04 0.2950 0.3928 0.2954 0.0722 0.2945 0.3927 0.2978 0.0759

2.89E-05 2.70E-04 0.2988 0.3932 0.2883 0.0620 0.3026 0.3980 0.2935 0.0649

2.89E-05 3.20E-04 0.3011 0.3947 0.2868 0.0588 0.3069 0.4008 0.2912 0.0592


223

[2.1] (M) [2.3Me]

(M)



2.89E-05 0 0.1432 0.2923 0.3716 0.2706 0.1432 0.2923 0.3716 0.2706

2.89E-05 1.21E-05 0.1670 0.3134 0.3676 0.2465 0.1670 0.3087 0.3586 0.2374

2.89E-05 5.02E-05 0.2212 0.3519 0.3425 0.1746 0.2170 0.3432 0.3313 0.1676

2.89E-05 8.48E-05 0.2445 0.3636 0.3203 0.1334 0.2426 0.3609 0.3173 0.1318

2.89E-05 1.16E-04 0.2580 0.3723 0.3090 0.1088 0.2574 0.3711 0.3092 0.1111

2.89E-05 1.64E-04 0.2733 0.3830 0.3005 0.0877 0.2718 0.3810 0.3014 0.0910

2.89E-05 2.13E-04 0.2844 0.3904 0.2968 0.0773 0.2810 0.3874 0.2964 0.0782

2.89E-05 2.74E-04 0.2888 0.3920 0.2912 0.0661 0.2885 0.3926 0.2923 0.0677

2.89E-05 3.24E-04 0.2889 0.3908 0.2861 0.0608 0.2927 0.3955 0.2899 0.0617



[2.1] (M) [2.4Me]

(M)



3.11E-05 0 0.1500 0.3331 0.4694 0.3449 0.1500 0.3331 0.4694 0.3449

3.11E-05 8.54E-06 0.2002 0.3737 0.4474 0.2858 0.2023 0.3695 0.4352 0.2779

3.11E-05 1.69E-05 0.2448 0.3983 0.4081 0.2222 0.2472 0.4006 0.4059 0.2204

3.11E-05 2.51E-05 0.2832 0.4270 0.3859 0.1767 0.2829 0.4254 0.3825 0.1746

3.11E-05 3.32E-05 0.3092 0.4438 0.3650 0.1400 0.3093 0.4437 0.3653 0.1408

3.11E-05 4.11E-05 0.3276 0.4547 0.3502 0.1151 0.3277 0.4565 0.3532 0.1171

3.11E-05 6.02E-05 0.3538 0.4718 0.3323 0.0818 0.3530 0.4740 0.3367 0.0847

3.11E-05 7.85E-05 0.3648 0.4790 0.3240 0.0671 0.3646 0.4821 0.3291 0.0699

3.11E-05 1.13E-04 0.3767 0.4884 0.3208 0.0575 0.3749 0.4892 0.3224 0.0567

3.11E-05 1.73E-04 0.3819 0.4941 0.3166 0.0461 0.3820 0.4942 0.3177 0.0475

3.11E-05 2.47E-04 0.3839 0.4963 0.3147 0.0422 0.3856 0.4967 0.3154 0.0429

3.11E-05 3.40E-04 0.3876 0.5013 0.3169 0.0404 0.3878 0.4982 0.3139 0.0401


224

[2.1] (M) [2.4Me]

(M)



2.89E-05 0 0.1465 0.3307 0.4574 0.3349 0.1465 0.3307 0.4574 0.3349

2.89E-05 3.58E-06 0.1672 0.3445 0.4462 0.3107 0.1666 0.3439 0.4433 0.3079

2.89E-05 7.12E-06 0.1865 0.3534 0.4282 0.2820 0.1854 0.3562 0.4302 0.2827

2.89E-05 1.06E-05 0.2061 0.3672 0.4179 0.2583 0.2028 0.3676 0.4180 0.2593

2.89E-05 1.41E-05 0.2226 0.3789 0.4082 0.2374 0.2187 0.3781 0.4068 0.2378

2.89E-05 2.09E-05 0.2467 0.3944 0.3869 0.1993 0.2462 0.3961 0.3876 0.2008

2.89E-05 2.77E-05 0.2709 0.4101 0.3740 0.1732 0.2682 0.4105 0.3723 0.1713

2.89E-05 3.42E-05 0.2866 0.4209 0.3610 0.1500 0.2852 0.4217 0.3603 0.1484

2.89E-05 5.02E-05 0.3119 0.4378 0.3410 0.1126 0.3125 0.4397 0.3412 0.1116

2.89E-05 6.54E-05 0.3275 0.4485 0.3303 0.0919 0.3274 0.4495 0.3308 0.0915

2.89E-05 9.38E-05 0.3408 0.4563 0.3178 0.0711 0.3422 0.4591 0.3205 0.0717

2.89E-05 1.20E-04 0.3500 0.4642 0.3148 0.0618 0.3492 0.4638 0.3155 0.0622

2.89E-05 1.66E-04 0.3548 0.4679 0.3093 0.0516 0.3559 0.4681 0.3109 0.0532

2.89E-05 2.05E-04 0.3572 0.4702 0.3075 0.0472 0.3591 0.4702 0.3086 0.0489

2.89E-05 2.83E-04 0.3618 0.4755 0.3079 0.0447 0.3627 0.4726 0.3061 0.0441


225


[2.1] (M) [2.5Me]

(M)



2.44E-05 0 0.1314 0.2535 0.3043 0.2224 0.1314 0.2535 0.3043 0.2224

2.44E-05 2.64E-04 0.1514 0.2561 0.2923 0.1953 0.1590 0.2628 0.2911 0.1952

2.44E-05 5.03E-04 0.1791 0.2689 0.2842 0.1765 0.1795 0.2697 0.2813 0.1748

2.44E-05 7.22E-04 0.1963 0.2730 0.2716 0.1566 0.1954 0.2750 0.2737 0.1591

2.44E-05 9.23E-04 0.2071 0.2756 0.2635 0.1431 0.2081 0.2793 0.2677 0.1466

2.44E-05 1.11E-03 0.2199 0.2811 0.2590 0.1332 0.2184 0.2828 0.2627 0.1363

2.44E-05 1.44E-03 0.2365 0.2912 0.2567 0.1218 0.2343 0.2881 0.2551 0.1207


[2.1] (M) [2.5Me]

(M)



1.47E-05 0 0.0876 0.1668 0.1997 0.1456 0.0876 0.1668 0.1997 0.1456

1.47E-05 2.44E-04 0.1062 0.1741 0.1917 0.1215 0.1061 0.1707 0.1852 0.1202

1.47E-05 4.65E-04 0.1183 0.1759 0.1794 0.1029 0.1181 0.1733 0.1758 0.1038

1.47E-05 6.68E-04 0.1275 0.1769 0.1708 0.0916 0.1265 0.1750 0.1692 0.0922

1.47E-05 8.53E-04 0.1352 0.1787 0.1659 0.0835 0.1327 0.1763 0.1643 0.0837

1.47E-05 1.02E-03 0.1383 0.1776 0.1593 0.0757 0.1375 0.1774 0.1606 0.0771

1.47E-05 1.18E-03 0.1410 0.1770 0.1559 0.0708 0.1413 0.1782 0.1576 0.0719

1.47E-05 1.46E-03 0.1461 0.1779 0.1520 0.0651 0.1469 0.1793 0.1532 0.0641


226

Table S9. Observed UV-vis Data and the Corresponding Nonlinear Fits for 2.5H.

[2.1] (M) [2.5H]

(M)



2.44E-05 0 0.1293 0.2690 0.3521 0.2575 0.1293 0.2690 0.3521 0.2575

2.44E-05 1.13E-05 0.1914 0.2949 0.3036 0.1752 0.1829 0.2991 0.3139 0.1813

2.44E-05 2.22E-05 0.2269 0.3184 0.2837 0.1278 0.2211 0.3205 0.2868 0.1269

2.44E-05 3.29E-05 0.2437 0.3295 0.2703 0.0990 0.2432 0.3329 0.2711 0.0956

2.44E-05 4.66E-05 0.2569 0.3397 0.2631 0.0808 0.2575 0.3409 0.2609 0.0752

2.44E-05 6.94E-05 0.2684 0.3506 0.2594 0.0651 0.2675 0.3465 0.2538 0.0610

2.44E-05 9.96E-05 0.2700 0.3505 0.2507 0.0515 0.2728 0.3495 0.2500 0.0535

2.44E-05 1.53E-04 0.2742 0.3531 0.2473 0.0448 0.2765 0.3516 0.2474 0.0483


[2.1] (M) [2.5H]

(M)



2.44E-05 0 0.1310 0.2716 0.3553 0.2598 0.1310 0.2716 0.3553 0.2598

2.44E-05 9.40E-06 0.1808 0.2896 0.3142 0.1932 0.1737 0.2947 0.3231 0.1973

2.44E-05 1.85E-05 0.2124 0.3084 0.2935 0.1491 0.2065 0.3124 0.2984 0.1493

2.44E-05 3.03E-05 0.2357 0.3234 0.2762 0.1124 0.2342 0.3273 0.2775 0.1089

2.44E-05 4.44E-05 0.2525 0.3364 0.2674 0.0888 0.2515 0.3366 0.2645 0.0836

2.44E-05 7.07E-05 0.2655 0.3465 0.2584 0.0669 0.2648 0.3439 0.2544 0.0641

2.44E-05 1.06E-04 0.2713 0.3495 0.2506 0.0535 0.2714 0.3474 0.2495 0.0544

2.44E-05 1.47E-04 0.2734 0.3513 0.2474 0.0471 0.2748 0.3492 0.2470 0.0496

2.44E-05 1.82E-04 0.2749 0.3517 0.2462 0.0458 0.2763 0.3500 0.2458 0.0473


227


[2.1] (M) [2.2H]

(M)



2.89E-05 0 0.0304 0.1128 0.4692 0.3438 0.0304 0.1128 0.4692 0.3438

2.89E-05 3.63E-06 0.0645 0.1646 0.4179 0.2947 0.0724 0.1899 0.3959 0.2783

2.89E-05 7.22E-06 0.1082 0.2283 0.3518 0.2354 0.1089 0.2508 0.3361 0.2261

2.89E-05 1.08E-05 0.1490 0.2867 0.2888 0.1816 0.1405 0.2987 0.2875 0.1848

2.89E-05 1.43E-05 0.1812 0.3295 0.2381 0.1405 0.1679 0.3361 0.2479 0.1521

2.89E-05 2.13E-05 0.2301 0.3919 0.1758 0.0936 0.2123 0.3876 0.1895 0.1062

2.89E-05 2.81E-05 0.2601 0.4228 0.1378 0.0695 0.2464 0.4184 0.1503 0.0778

2.89E-05 4.45E-05 0.2988 0.4536 0.0977 0.0482 0.3029 0.4497 0.0977 0.0460

2.89E-05 6.02E-05 0.3209 0.4630 0.0808 0.0441 0.3367 0.4544 0.0751 0.0379

2.89E-05 8.96E-05 0.3506 0.4603 0.0676 0.0467 0.3744 0.4447 0.0594 0.0404

2.89E-05 1.17E-04 0.3743 0.4476 0.0632 0.0528 0.3947 0.4321 0.0557 0.0475

2.89E-05 1.68E-04 0.4144 0.4118 0.0598 0.0669 0.4172 0.4110 0.0560 0.0609

2.89E-05 2.08E-04 0.4322 0.3901 0.0591 0.0744 0.4275 0.3987 0.0578 0.0691

2.89E-05 2.43E-04 0.4423 0.3796 0.0605 0.0795 0.4338 0.3902 0.0595 0.0749

2.89E-05 3.13E-04 0.4503 0.3646 0.0596 0.0832 0.4425 0.3775 0.0626 0.0836

2.89E-05 3.65E-04 0.4568 0.3614 0.0616 0.0857 0.4469 0.3705 0.0645 0.0884


228

[2.1] (M) [2.2H]

(M)



2.89E-05 0 0.0316 0.1130 0.4627 0.3399 0.0316 0.1130 0.4627 0.3399

2.89E-05 4.15E-06 0.0768 0.1821 0.3976 0.2772 0.0814 0.2042 0.3760 0.2617

2.89E-05 8.26E-06 0.1297 0.2564 0.3186 0.2081 0.1241 0.2731 0.3079 0.2021

2.89E-05 1.23E-05 0.1715 0.3179 0.2569 0.1536 0.1605 0.3242 0.2549 0.1575

2.89E-05 1.64E-05 0.2053 0.3615 0.2047 0.1125 0.1915 0.3617 0.2139 0.1244

2.89E-05 2.43E-05 0.2513 0.4137 0.1471 0.0732 0.2402 0.4085 0.1574 0.0821

2.89E-05 3.21E-05 0.2792 0.4383 0.1179 0.0567 0.2761 0.4324 0.1228 0.0595

2.89E-05 3.97E-05 0.2980 0.4488 0.0989 0.0483 0.3033 0.4439 0.1011 0.0478

2.89E-05 5.82E-05 0.3310 0.4580 0.0797 0.0464 0.3481 0.4495 0.0741 0.0391

2.89E-05 9.27E-05 0.3703 0.4471 0.0644 0.0511 0.3927 0.4371 0.0593 0.0451

2.89E-05 1.39E-04 0.4120 0.4190 0.0601 0.0640 0.4220 0.4184 0.0566 0.0575

2.89E-05 2.16E-04 0.4491 0.3861 0.0593 0.0780 0.4448 0.3976 0.0587 0.0723

2.89E-05 2.78E-04 0.4605 0.3758 0.0597 0.0813 0.4545 0.3871 0.0607 0.0798

2.89E-05 3.57E-04 0.4679 0.3701 0.0616 0.0850 0.4621 0.3780 0.0627 0.0865

2.89E-05 4.17E-04 0.4728 0.3692 0.0631 0.0875 0.4661 0.3731 0.0640 0.0901


229


[2.1] (M) [2.3H]

(M)



2.44E-05 0 0.1451 0.2999 0.3874 0.2847 0.1451 0.2999 0.3874 0.2847

2.44E-05 4.25E-06 0.1623 0.3079 0.3797 0.2686 0.1643 0.3108 0.3752 0.2587

2.44E-05 8.46E-06 0.1803 0.3189 0.3725 0.2508 0.1816 0.3206 0.3643 0.2353

2.44E-05 1.26E-05 0.1952 0.3240 0.3569 0.2261 0.1970 0.3294 0.3545 0.2144

2.44E-05 1.68E-05 0.2113 0.3347 0.3498 0.2059 0.2106 0.3371 0.3459 0.1961

2.44E-05 2.08E-05 0.2245 0.3413 0.3403 0.1866 0.2224 0.3438 0.3384 0.1800

2.44E-05 2.49E-05 0.2364 0.3490 0.3322 0.1697 0.2328 0.3497 0.3319 0.1660

2.44E-05 3.29E-05 0.2547 0.3586 0.3189 0.1439 0.2496 0.3592 0.3212 0.1432

2.44E-05 4.07E-05 0.2674 0.3666 0.3093 0.1221 0.2623 0.3664 0.3132 0.1261

2.44E-05 5.22E-05 0.2814 0.3769 0.3015 0.1019 0.2759 0.3742 0.3046 0.1076

2.44E-05 7.06E-05 0.2931 0.3842 0.2917 0.0801 0.2902 0.3822 0.2956 0.0884

2.44E-05 1.05E-04 0.3068 0.3956 0.2878 0.0650 0.3044 0.3903 0.2866 0.0691

2.44E-05 1.36E-04 0.3064 0.3929 0.2799 0.0546 0.3113 0.3942 0.2822 0.0598

2.44E-05 1.92E-04 0.3148 0.4003 0.2821 0.0536 0.3180 0.3980 0.2780 0.0507


230

[2.1] (M) [2.3H]

(M)



2.44E-05 0 0.1478 0.3076 0.3976 0.2923 0.1478 0.3076 0.3976 0.2923

2.44E-05 4.67E-06 0.1639 0.3082 0.3790 0.2690 0.1669 0.3170 0.3829 0.2640

2.44E-05 9.29E-06 0.1796 0.3168 0.3686 0.2468 0.1839 0.3254 0.3699 0.2389

2.44E-05 1.39E-05 0.1961 0.3259 0.3593 0.2267 0.1989 0.3328 0.3583 0.2167

2.44E-05 2.29E-05 0.2266 0.3419 0.3407 0.1884 0.2233 0.3448 0.3396 0.1806

2.44E-05 3.61E-05 0.2515 0.3514 0.3139 0.1419 0.2488 0.3574 0.3200 0.1428

2.44E-05 5.73E-05 0.2779 0.3693 0.2969 0.1015 0.2733 0.3695 0.3012 0.1066

2.44E-05 8.53E-05 0.2960 0.3841 0.2883 0.0759 0.2902 0.3778 0.2883 0.0816

2.44E-05 1.22E-04 0.3036 0.3882 0.2794 0.0598 0.3015 0.3834 0.2796 0.0649

2.44E-05 1.88E-04 0.3085 0.3917 0.2773 0.0526 0.3107 0.3879 0.2725 0.0512


231


[2.1] (M) [2.4H]

(M)



2.44E-05 0 0.1595 0.3198 0.4019 0.2958 0.1595 0.3198 0.4019 0.2958

2.44E-05 3.84E-06 0.1766 0.3277 0.3901 0.2723 0.1837 0.3279 0.3844 0.2665

2.44E-05 7.64E-06 0.1959 0.3339 0.3763 0.2494 0.2052 0.3347 0.3684 0.2403

2.44E-05 1.14E-05 0.2146 0.3385 0.3594 0.2227 0.2242 0.3405 0.3539 0.2168

2.44E-05 1.88E-05 0.2500 0.3487 0.3312 0.1786 0.2554 0.3492 0.3287 0.1772

2.44E-05 2.61E-05 0.2781 0.3542 0.3049 0.1412 0.2793 0.3548 0.3081 0.1459

2.44E-05 3.67E-05 0.3073 0.3599 0.2783 0.1024 0.3045 0.3592 0.2840 0.1111

2.44E-05 5.38E-05 0.3316 0.3605 0.2526 0.0704 0.3277 0.3599 0.2568 0.0752

2.44E-05 7.01E-05 0.3391 0.3564 0.2375 0.0542 0.3378 0.3566 0.2397 0.0557

2.44E-05 1.01E-04 0.3450 0.3502 0.2249 0.0435 0.3419 0.3474 0.2211 0.0391

2.44E-05 1.29E-04 0.3426 0.3425 0.2173 0.0388 0.3392 0.3390 0.2120 0.0341

2.44E-05 1.78E-04 0.3330 0.3268 0.2054 0.0353 0.3315 0.3270 0.2038 0.0331

2.44E-05 2.57E-04 0.3221 0.3122 0.1983 0.0391 0.3207 0.3145 0.1984 0.0361

2.44E-05 3.31E-04 0.3130 0.3025 0.1941 0.0416 0.3137 0.3073 0.1961 0.0391

2.44E-05 3.86E-04 0.3042 0.2941 0.1896 0.0414 0.3098 0.3034 0.1952 0.0410


232

[2.1] (M) [2.4H]

(M)



2.44E-05 0 0.1603 0.3189 0.3995 0.2951 0.1603 0.3189 0.3995 0.2951

2.44E-05 4.67E-06 0.1859 0.3303 0.3827 0.2616 0.1931 0.3295 0.3753 0.2548

2.44E-05 9.29E-06 0.2166 0.3410 0.3623 0.2263 0.2219 0.3384 0.3536 0.2192

2.44E-05 1.39E-05 0.2433 0.3478 0.3393 0.1904 0.2466 0.3457 0.3344 0.1883

2.44E-05 1.84E-05 0.2664 0.3515 0.3173 0.1592 0.2673 0.3514 0.3178 0.1619

2.44E-05 2.29E-05 0.2860 0.3546 0.2976 0.1325 0.2843 0.3557 0.3034 0.1396

2.44E-05 4.47E-05 0.3299 0.3597 0.2529 0.0718 0.3300 0.3621 0.2579 0.0749

2.44E-05 8.53E-05 0.3463 0.3530 0.2278 0.0449 0.3441 0.3514 0.2255 0.0414

2.44E-05 1.56E-04 0.3409 0.3359 0.2119 0.0377 0.3351 0.3322 0.2089 0.0353

2.44E-05 2.43E-04 0.3294 0.3213 0.2038 0.0382 0.3249 0.3190 0.2022 0.0373

2.44E-05 3.13E-04 0.3205 0.3113 0.1990 0.0400 0.3195 0.3127 0.1997 0.0391

2.44E-05 4.02E-04 0.3087 0.2975 0.1907 0.0400 0.3148 0.3075 0.1978 0.0409

2.44E-05 4.69E-04 0.3057 0.2945 0.1909 0.0421 0.3123 0.3047 0.1969 0.0419


233

Table S13. Observed UV-vis Data and the Corresponding Nonlinear Fits for 2.6.

[2.1] (M) [2.6] (M) Observed Absorbance Calculated Absorbancea


2.89E-05 0 0.0596 0.1701 0.3786 0.2779 0.0596 0.1701 0.3786 0.2779

2.89E-05 5.93E-06 0.1361 0.2242 0.3001 0.2001 0.1324 0.2217 0.2997 0.1996

2.89E-05 1.18E-05 0.1817 0.2557 0.2460 0.1469 0.1796 0.2549 0.2489 0.1479

2.89E-05 1.76E-05 0.2052 0.2714 0.2222 0.1222 0.2046 0.2723 0.2223 0.1195

2.89E-05 2.34E-05 0.2162 0.2797 0.2088 0.1058 0.2180 0.2816 0.2082 0.1035

2.89E-05 2.91E-05 0.2239 0.2852 0.1980 0.0930 0.2259 0.2870 0.2000 0.0936

2.89E-05 4.03E-05 0.2335 0.2919 0.1907 0.0822 0.2346 0.2928 0.1913 0.0819

2.89E-05 5.67E-05 0.2404 0.2973 0.1862 0.0723 0.2405 0.2965 0.1857 0.0727

2.89E-05 8.31E-05 0.2450 0.3005 0.1843 0.0647 0.2442 0.2987 0.1826 0.0652

2.89E-05 1.08E-04 0.2451 0.2982 0.1815 0.0588 0.2454 0.2992 0.1819 0.0612

2.89E-05 1.55E-04 0.2458 0.3000 0.1843 0.0557 0.2457 0.2989 0.1826 0.0569

2.89E-05 1.99E-04 0.2453 0.2990 0.1850 0.0531 0.2452 0.2981 0.1839 0.0546

2.89E-05 2.75E-04 0.2439 0.2982 0.1876 0.0517 0.2438 0.2966 0.1865 0.0523

2.89E-05 3.40E-04 0.2438 0.2968 0.1918 0.0522 0.2425 0.2953 0.1886 0.0511

2.89E-05 3.97E-04 0.2408 0.2942 0.1903 0.0504 0.2414 0.2943 0.1903 0.0504

2.89E-05 5.11E-04 0.2386 0.2909 0.1914 0.0496 0.2394 0.2924 0.1933 0.0494


234

[2.1] (M) [2.6] (M) Observed Absorbance Calculated Absorbancea


2.89E-05 0 0.0626 0.1750 0.3866 0.2839 0.0626 0.1750 0.3866 0.2839

2.89E-05 6.54E-06 0.1457 0.2333 0.2913 0.1909 0.1428 0.2322 0.2962 0.1933

2.89E-05 1.30E-05 0.1937 0.2648 0.2368 0.1368 0.1926 0.2671 0.2405 0.1359

2.89E-05 1.94E-05 0.2175 0.2824 0.2141 0.1103 0.2162 0.2832 0.2145 0.1077

2.89E-05 2.58E-05 0.2301 0.2921 0.2049 0.0982 0.2279 0.2909 0.2019 0.0931

2.89E-05 3.21E-05 0.2332 0.2924 0.1944 0.0848 0.2345 0.2950 0.1950 0.0843

2.89E-05 4.45E-05 0.2420 0.2987 0.1888 0.0750 0.2416 0.2991 0.1879 0.0743

2.89E-05 6.26E-05 0.2463 0.3012 0.1837 0.0657 0.2463 0.3013 0.1836 0.0666

2.89E-05 9.17E-05 0.2475 0.3015 0.1814 0.0581 0.2493 0.3020 0.1815 0.0604

2.89E-05 1.20E-04 0.2480 0.3013 0.1811 0.0530 0.2504 0.3018 0.1813 0.0571

2.89E-05 1.72E-04 0.2506 0.3035 0.1845 0.0527 0.2508 0.3006 0.1821 0.0536

2.89E-05 2.19E-04 0.2496 0.3027 0.1854 0.0495 0.2506 0.2994 0.1834 0.0518

2.89E-05 3.03E-04 0.2471 0.2999 0.1873 0.0469 0.2498 0.2975 0.1855 0.0499

2.89E-05 3.76E-04 0.2472 0.2996 0.1898 0.0478 0.2490 0.2961 0.1872 0.0489

2.89E-05 4.38E-04 0.2455 0.2972 0.1905 0.0460 0.2484 0.2950 0.1885 0.0483

2.89E-05 5.64E-04 0.2498 0.2874 0.1858 0.0504 0.2472 0.2931 0.1908 0.0475


235

Representative Calculations of λmax1:1

For compounds that were best fit by the 1:1 binding model (2.3Me, 2.4Me, 2.5Me, 2.5H,

and 2.3H), λmax of the 1:1 complex was observed when additional amounts of the Brønsted

acid during the titration led to no further change in λmax. For other compounds that exhibited

additional equilibria (2.2Me, 2.2H, 2.4H, and 2.6), this endpoint was less clear. In the

output file downloaded from the BindFit program, the mole fractions of each species were

provided (i.e., free 1 and the 1:1, 1:2, or 2:1 complexes). A linear relationship was

observed between the mole fraction of the 1:1 complex (x1:1) and the observed λmax at

each titration point with the following expression:

1000 (𝑥1:1

𝜆𝑚𝑎𝑥) = 𝑚𝑥1:1 + 𝑏

Thus, when x1:1 = 1,

1000

𝜆𝑚𝑎𝑥= 𝑚 + 𝑏 or 𝜆𝑚𝑎𝑥 =

1000

𝑚+𝑏

This relationship was employed for each compound to obtain λmax, and the results for the

catalysts that were best fit with a 1:1 binding model are in excellent accord with the

observed leveled-off values (i.e., ±1 nm).

2.2Me

x1:1 λmax (nm)

0 499.8

0.0486 497.3

0.0940 495.2

0.1364 489.1

0.1759 480.9

0.2127 449.1

0.2470 444.0

0.2790 439.2

0.3087 435.8

0.3364 432.1

0.3622 431.8

0.4494 428.1

0.5306 426.8

0.6008 424.5

0.6783 422.6

0.7468 419.2

0.7977 416.1

0.8388 413.0

0.8618 410.8

0.8766 410.0

0.8896 408.7

0.9435 407.3

y = 2.4753x - 0.0493R² = 0.9994

0.00

0.50

1.00

1.50

2.00

2.50

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

236

2.3Me

x1:1 λmax (nm)

0 499.8

0.0885 497.9

0.1654 495.8

0.2323 493.8

0.2905 491.0

0.3414 484.7

0.4427 480.0

0.5173 476.7

0.5737 475.5

0.6175 475.6

0.6804 473.8

0.7539 472.3

0.7950 472.0

0.8391 471.5

0.8623 471.7

0.8766 471.7

2.4Me

x1:1 λmax (nm)

0 499.3

0.2154 494.8

0.3999 484.2

0.5469 473.8

0.6554 470.0

0.7315 469.0

0.8355 467.9

0.8832 466.1

0.9255 465.8

0.9550 465.2

0.9698 464.9

0.9787 465.8

0.9825 465.2

y = 2.137x - 0.0179R² = 0.9999

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

y = 2.1688x - 0.0232R² = 0.9998

0.00

0.50

1.00

1.50

2.00

2.50

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

237

2.5Me

x1:1 λmax (nm)

0 499.8

0.1746 495.9

0.2880 495.2

0.3675 481.3

0.4262 480.7

0.4714 476.7

0.5073 476.8

0.5606 475.0

0.5899 474.8

2.5H

x1:1 λmax (nm)

0 499.8

0.3507 486.2

0.6007 475.5

0.7449 471.9

0.8385 471.3

0.9040 470.9

0.9384 469.2

0.9625 469.3

0.9719 469.3

y = 2.14x - 0.0137R² = 0.9999

0.00

0.50

1.00

1.50

2.00

2.50

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

y = 2.119x - 0.0127R² = 0.9996

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7(x

1:1

/ λ m

ax)

x 1

03

x1:1

238

2.2H

2.3H

x1:1 λmax (nm)

0 499.2

0.1018 498.2

0.1934 496.1

0.2750 493.9

0.3469 487.6

0.4099 483.8

0.4647 479.7

0.5536 476.0

0.6208 474.1

0.6931 473.3

0.7685 471.7

0.8439 470.7

0.8805 470.3

0.9158 470.4

0.9385 470.3

x1:1 λmax (nm)

0 499.8

0.0557 496.8

0.1079 492.9

0.1564 451.2

0.2013 444.2

0.2803 431.0

0.3467 428.4

0.4705 426.3

0.5540 424.4

0.6574 422.0

0.7181 419.3

0.7903 413.7

0.8250 410.0

0.8470 408.0

0.8778 406.8

0.8938 406.2

0.9447 405.9

y = 2.4816x - 0.0413R² = 0.9993

0.00

0.50

1.00

1.50

2.00

2.50

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

y = 2.1448x - 0.0214R² = 0.9998

0.00

0.50

1.00

1.50

2.00

2.50

0.0 0.2 0.4 0.6 0.8 1.0

(x1:1

/ λ m

ax)

x 1

03

x1:1

239

2.4H

x1:1 λmax (nm)

0 500.0

0.0850 497.0

0.1587 495.8

0.2223 493.8

0.3233 483.9

0.3955 472.3

0.4634 468.9

0.5088 463.0

0.5104 461.6

0.4707 460.3

0.4229 458.2

0.3480 455.9

0.2648 453.5

0.2150 451.8

0.1880 454.5

0.0993 463.4

2.6

x1:1 λmax (nm)

0 499.8

0.0236 493.5

0.0552 471.3

0.0869 450.8

0.1146 449.8

0.1385 447.0

0.1776 446.2

0.2227 446.4

0.2776 444.9

0.3185 444.9

0.3779 446.1

0.4202 446.5

0.4784 446.2

0.5174 447.7

0.5458 449.8

0.5920 450.5

0.6200 450.9

y = 2.2295x + 0.0002R² = 0.9999

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

(x1:1

/ λ m

ax)

x 1

03

x1:1

y = 2.1716x - 0.0074R² = 0.9983

0.00

0.20

0.40

0.60

0.80

1.00

1.20

0.0 0.1 0.2 0.3 0.4 0.5 0.6

(x1:1

/ λ m

ax)

x 1

03

x1:1

240

NMR spectra

1H NMR in CD2Cl2

NMR Solvent

241

13C NMR in CD2Cl2

NMR Solvent

242

1H NMR in CD3CN

NMR Solvent

243

13C NMR in CD3CN

NMR Solvent

NMR Solvent

244

1H NMR in CD2Cl2 of 2.3Me

NMR Solvent

245

13C NMR in d6-DMSO of 2.3Me

NMR Solvent

246

19F NMR in CD2Cl2 of 2.3Me

Fluorobenzene

247

1H NMR in CD3CN

NMR Solvent

248

13C NMR in CD3CN

NMR Solvent

249

19F NMR in CD3CN

Fluorobenzene

250


NMR Solvent

251

13C NMR in CD2Cl2 of 2.2Me

NMR Solvent

252


Fluorobenzene

253

1H NMR in CD3CN

NMR Solvent

254

13C NMR in CD3CN

NMR Solvent

NMR Solvent

255

19F NMR in CD3CN

Fluorobenzene

256

1H NMR in CD2Cl2 of 2.4H

NMR Solvent

257

13C NMR in CD2Cl2 of 2.4H

NMR Solvent

258

19F NMR in CD2Cl2 of 2.4H

Fluorobenzene

259


NMR Solvent

260


NMR Solvent

261


Fluorobenzene

262


NMR Solvent

263


NMR Solvent

264


Fluorobenzene

265


NMR Solvent

266

13C NMR in d6-DMSO of 2.3H

NMR Solvent

267


Fluorobenzene

268


NMR Solvent

269


NMR Solvent

270


Fluorobenzene

271


NMR Solvent

272


NMR Solvent

273


Fluorobenzene

274

1H NMR in CD2Cl2 of 2.6

NMR Solvent

275

13C NMR in CD2Cl2 of 2.6

NMR Solvent

276

19F NMR in CD2Cl2 of 2.6

Fluorobenzene

277

2.2Me

G4 enthalpy = -362.976176, S = 81.627, 3791.7 cm–1 O–H stretch, no imaginary

frequencies

1 6 0 -1.352098 0.651688 0.000000 2 6 0 0.812481 -0.282876 0.000000 3 6 0 0.269793 -1.567761 0.000000 4 6 0 -1.103962 -1.720483 0.000000 5 6 0 -1.931994 -0.590732 0.000000 6 1 0 -1.923582 1.569950 0.000000 7 1 0 0.936793 -2.421853 0.000000 8 1 0 -1.535407 -2.715032 0.000000 9 1 0 -3.010351 -0.676353 0.000000 10 7 0 0.000000 0.803343 0.000000 11 8 0 2.103777 0.011842 0.000000 12 1 0 2.653776 -0.783298 0.000000 13 6 0 0.605170 2.154984 0.000000 14 1 0 1.224842 2.275177 0.889414 15 1 0 1.224842 2.275177 -0.889414 16 1 0 -0.197468 2.889166 0.000000

2.2Me conjugate base

G4 enthalpy = -362.622650, S = 81.763, no imaginary frequencies

1 6 0 1.344847 0.597593 0.000000 2 6 0 -0.950107 -0.246668 0.000000 3 6 0 -0.362748 -1.568376 0.000000 4 6 0 0.985674 -1.761190 0.000000 5 6 0 1.876984 -0.655892 0.000000 6 1 0 1.958644 1.490827 0.000000 7 1 0 -1.065375 -2.392447 0.000000 8 1 0 1.388049 -2.769824 0.000000 9 1 0 2.950087 -0.788591 0.000000 10 7 0 0.000000 0.808501 0.000000 11 8 0 -2.144050 0.021780 0.000000 12 6 0 -0.555679 2.157908 0.000000 13 1 0 -1.186230 2.301932 0.880490 14 1 0 0.259631 2.882178 0.000000 15 1 0 -1.186230 2.301932 -0.880490

278

2.3Me


frequencies

1 6 0 -1.095588 1.139598 -0.007432 2 6 0 0.127675 1.786874 0.002734 3 6 0 1.304241 1.051704 0.006276 4 6 0 1.237627 -0.347768 0.000543 5 6 0 -0.019437 -0.951884 -0.009831 6 7 0 -1.141245 -0.208302 -0.013849 7 1 0 2.266023 1.554772 0.011306 8 1 0 -2.042939 1.659732 -0.010692 9 1 0 0.149419 2.869336 0.004768 10 1 0 -0.127220 -2.028304 -0.015403 11 6 0 -2.451188 -0.901300 0.013010 12 1 0 -3.222317 -0.216255 -0.334826 13 1 0 -2.408869 -1.768414 -0.645720 14 1 0 -2.668086 -1.218384 1.035142 15 8 0 2.287230 -1.170922 0.001717 16 1 0 3.124880 -0.690328 0.006845

2.3Me conjugate base


1 6 0 -1.031979 1.157468 -0.012607 2 6 0 0.227796 1.754164 0.004474 3 6 0 1.376750 0.998918 0.009983 4 6 0 1.342372 -0.453905 0.000516 5 6 0 -0.011486 -0.975330 -0.018483 6 7 0 -1.102579 -0.193342 -0.023029 7 1 0 2.353748 1.470486 0.020068 8 1 0 -1.965833 1.698002 -0.014825 9 1 0 0.276578 2.837889 0.008755 10 1 0 -0.175111 -2.045247 -0.027319 11 8 0 2.330531 -1.194869 0.005843 12 6 0 -2.427882 -0.829155 0.022167 13 1 0 -2.390868 -1.776147 -0.516208 14 1 0 -2.719138 -1.011511 1.059550

279

15 1 0 -3.158999 -0.174084 -0.451870

2.4Me


frequencies

1 6 0 0.642226 -1.168341 -0.007722 2 6 0 0.626663 1.175775 -0.007506 3 6 0 -0.746756 1.201301 -0.001149 4 6 0 -1.456492 -0.011631 0.002457 5 6 0 -0.725737 -1.214837 -0.000992 6 1 0 1.251306 -2.063245 -0.010821 7 1 0 -1.257518 2.157134 -0.001570 8 1 0 -1.244395 -2.164778 -0.001026 9 7 0 1.313612 0.011623 -0.011858 10 6 0 2.791829 0.007515 0.013917 11 1 0 3.156238 0.998358 -0.252610 12 1 0 3.140818 -0.255435 1.014808 13 1 0 3.161577 -0.718281 -0.711118 14 8 0 -2.775411 -0.102426 0.006668 15 1 0 1.217023 2.082717 -0.009957 16 1 0 -3.207442 0.762898 0.007930 2.4Me conjugate base


1 6 0 -0.015830 0.576307 1.180222 2 6 0 -0.015830 0.576307 -1.180222 3 6 0 -0.015830 -0.776178 -1.219141 4 6 0 -0.013348 -1.588173 0.000000 5 6 0 -0.015830 -0.776178 1.219141 6 1 0 -0.015251 1.187364 2.075935 7 1 0 -0.023068 -1.288878 -2.173412 8 1 0 -0.023068 -1.288878 2.173412 9 7 0 -0.023334 1.277843 -0.000000 10 6 0 0.083786 2.730195 -0.000000 11 1 0 -0.411532 3.134719 0.885106

280

12 1 0 1.129385 3.060280 -0.000000 13 1 0 -0.411532 3.134719 -0.885106 14 8 0 -0.013631 -2.815658 0.000000 15 1 0 -0.015251 1.187364 -2.075935

2.5H G4 enthalpy = -248.484282, S = 67.656, 3563.3 cm–1 N–H stretch, no imaginary frequencies 1 6 0 0.000000 1.186857 0.665422 2 6 0 0.000000 1.209011 -0.715294 3 6 0 -0.000000 0.000000 -1.412862 4 6 0 -0.000000 -1.209011 -0.715294 5 6 0 -0.000000 -1.186857 0.665422 6 7 0 0.000000 0.000000 1.306208 7 1 0 -0.000000 0.000000 -2.497232 8 1 0 0.000000 2.074229 1.285054 9 1 0 0.000000 2.160806 -1.231144 10 1 0 -0.000000 -2.160806 -1.231144 11 1 0 -0.000000 -2.074229 1.285054 12 1 0 0.000000 0.000000 2.321591 2.5H conjugate base (pyridine) G4 enthalpy = -248.132062, S = 67.243, no imaginary frequencies 1 6 0 0.000000 1.139912 0.720200 2 6 0 0.000000 1.195785 -0.671301 3 6 0 0.000000 -0.000000 -1.382205 4 6 0 -0.000000 -1.195785 -0.671301 5 6 0 -0.000000 -1.139912 0.720200 6 7 0 -0.000000 0.000000 1.417386 7 1 0 0.000000 -0.000000 -2.467329 8 1 0 0.000000 2.056748 1.305415 9 1 0 0.000000 2.153656 -1.179381 10 1 0 -0.000000 -2.153656 -1.179381 11 1 0 -0.000000 -2.056748 1.305415 2.5Me G4 enthalpy = -287.763754, S = 79.872, no imaginary frequencies 1 6 0 -0.007005 0.190847 1.174639

281

2 6 0 -0.007005 -1.189992 1.202049 3 6 0 -0.008080 -1.894733 0.000000 4 6 0 -0.007005 -1.189992 -1.202049 5 6 0 -0.007005 0.190847 -1.174639 6 1 0 -0.009643 -1.697915 2.158146 7 1 0 -0.010839 -2.978823 0.000000 8 1 0 -0.009643 -1.697915 -2.158146 9 1 0 -0.006627 0.797305 -2.071041 10 7 0 -0.007506 0.858545 -0.000000 11 6 0 0.032212 2.339358 -0.000000 12 1 0 1.072274 2.672899 -0.000000 13 1 0 -0.476513 2.709662 0.889163 14 1 0 -0.476513 2.709662 -0.889163 15 1 0 -0.006627 0.797305 2.071041 2.5Me conjugate base (– methyl proton) G4 enthalpy = -287.345237, S = 74.106, no imaginary frequencies 1 6 0 0.000000 1.180908 0.240690 2 6 0 0.000000 1.183381 -1.131699 3 6 0 -0.000000 0.000000 -1.872131 4 6 0 -0.000000 -1.183381 -1.131699 5 6 0 -0.000000 -1.180908 0.240690 6 1 0 0.000000 2.084838 0.833134 7 1 0 0.000000 2.150230 -1.624030 8 1 0 -0.000000 0.000000 -2.953078 9 1 0 -0.000000 -2.150230 -1.624030 10 1 0 -0.000000 -2.084838 0.833134 11 7 0 0.000000 -0.000000 0.983092 12 6 0 0.000000 -0.000000 2.317919 13 1 0 0.000000 -0.944278 2.835298 14 1 0 0.000000 0.944278 2.835298 2.5Me conjugate base (– ortho aryl proton) G4 enthalpy = -287.335838, S = 77.896, no imaginary frequencies 1 6 0 -1.284118 0.364654 0.000000 2 6 0 -1.300826 -1.063159 0.000000 3 6 0 -0.175152 -1.859499 0.000000 4 6 0 1.093436 -1.253663 0.000000 5 6 0 1.148292 0.112700 0.000000 6 1 0 -2.277411 -1.540620 0.000000

282

7 1 0 -0.249529 -2.944096 0.000000 8 1 0 2.008868 -1.832064 0.000000 9 1 0 2.083652 0.662041 0.000000 10 7 0 0.000000 0.850667 0.000000 11 6 0 0.161090 2.313357 0.000000 12 1 0 0.708871 2.637306 0.890528 13 1 0 -0.839654 2.739109 0.000000 14 1 0 0.708871 2.637306 -0.890528 2.2H G4 enthalpy = -323.696968, S = 74.205, 3789.0 and 3553.7 cm–1 O–H and N–H

stretches, respectively, no imaginary frequencies

1 6 0 -1.118062 -1.171628 0.000000 2 6 0 0.000000 0.933877 -0.000000 3 6 0 1.237462 0.289665 -0.000000 4 6 0 1.266422 -1.094532 -0.000000 5 6 0 0.077253 -1.842006 0.000000 6 1 0 -2.088078 -1.650872 0.000000 7 1 0 2.147034 0.878069 -0.000000 8 1 0 2.223196 -1.605068 -0.000000 9 1 0 0.089391 -2.923507 0.000000 10 7 0 -1.125049 0.186133 0.000000 11 8 0 -0.231276 2.233143 -0.000000 12 1 0 0.584301 2.753086 -0.000000 13 1 0 -2.008744 0.687953 0.000000 2.2H conjugate base (minus N–H proton) G4 enthalpy = -323.351033, S = 73.449, 3759.9 cm–1 O–H stretch, no imaginary

frequencies

1 6 0 -0.037962 -1.815599 0.000000 2 6 0 -1.188705 -1.042027 0.000000 3 6 0 0.000000 0.903216 0.000000 4 6 0 1.226981 0.228134 0.000000 5 6 0 1.193881 -1.155309 0.000000 6 1 0 -0.100117 -2.897004 0.000000

283

7 1 0 -2.170861 -1.508064 0.000000 8 1 0 2.152398 0.790282 0.000000 9 1 0 2.120511 -1.720107 0.000000 10 7 0 -1.180951 0.297640 0.000000 11 8 0 0.003392 2.252912 0.000000 12 1 0 -0.927579 2.517629 0.000000 2.2H conjugate base (minus O–H proton) G4 enthalpy = -323.349318, S = 73.945, 3605.8 cm–1 N–H stretch, no imaginary

frequencies

1 6 0 0.061993 -1.802359 -0.000000 2 6 0 -1.119472 -1.128592 -0.000000 3 6 0 -0.000000 1.069672 0.000000 4 6 0 1.244349 0.323124 0.000000 5 6 0 1.264953 -1.038987 -0.000000 6 1 0 0.076195 -2.883299 -0.000000 7 1 0 -2.086520 -1.617245 -0.000000 8 1 0 2.151962 0.913836 0.000000 9 1 0 2.217849 -1.560160 -0.000000 10 7 0 -1.136858 0.231707 -0.000000 11 8 0 -0.137151 2.281994 0.000000 12 1 0 -2.015203 0.731816 0.000000 2.3H G4 enthalpy = -323.688160, S = 74.302, 3797.4 and 3563.5 cm–1 O–H and N–H stretches, respectively, no imaginary frequencies

1 6 0 -1.111660 1.235289 -0.000011 2 6 0 -1.811827 0.042106 0.000035 3 6 0 0.228022 -1.178221 0.000011 4 6 0 0.971753 0.002474 0.000048 5 6 0 0.278120 1.222452 -0.000049 6 1 0 -1.656493 2.170769 -0.000234 7 1 0 -2.890058 -0.035160 0.000255 8 1 0 0.828912 2.158120 -0.000242 9 7 0 -1.113751 -1.109421 0.000021 10 8 0 2.296906 -0.131567 -0.000184 11 1 0 2.751280 0.720898 0.001532 12 1 0 0.689903 -2.156346 -0.000151 13 1 0 -1.628976 -1.984403 -0.000043 2.3H conjugate base (minus N–H proton) G4 enthalpy = -323.335668, S = 73.980, 3808.8 cm–1 O–H stretch, no imaginary

frequencies

1 6 0 1.193970 -1.143310 0.000000 2 6 0 -0.033994 -1.802725 0.000000

284

3 6 0 -1.178489 0.171850 0.000000 4 6 0 0.000000 0.923102 0.000000 5 6 0 1.217197 0.244456 0.000000 6 1 0 2.118560 -1.710266 0.000000 7 1 0 -0.079454 -2.888281 0.000000 8 1 0 2.144027 0.806978 0.000000 9 7 0 -1.203344 -1.159671 0.000000 10 8 0 0.011081 2.282748 0.000000 11 1 0 -0.896767 2.606435 0.000000 12 1 0 -2.143710 0.680602 0.000000 2.3H conjugate base (minus O–H proton) G4 enthalpy = -323.311533, S = 74.089, 3578.9 cm–1 N–H stretch, no imaginary

frequencies

1 6 0 1.182305 0.266147 0.000000 2 6 0 0.000000 1.106583 0.000000 3 6 0 -1.230560 0.327474 -0.000000 4 6 0 -1.240480 -1.049266 -0.000000 5 6 0 -0.051228 -1.776803 -0.000000 6 7 0 1.099714 -1.072011 0.000000 7 1 0 -2.160703 0.886350 -0.000000 8 1 0 2.173633 0.699712 0.000000 9 1 0 -2.177313 -1.595833 -0.000000 10 1 0 0.026152 -2.852801 0.000000 11 1 0 1.968115 -1.592282 0.000000 12 8 0 0.063987 2.339265 0.000000 2.4H G4 enthalpy = -323.697805, S = 74.064, 3772.4 and 3589.7 cm–1 O–H and N–H stretches, respectively, no imaginary frequencies

1 6 0 1.191712 -1.099046 0.000000 2 6 0 -1.176725 -1.108505 0.000000 3 6 0 -1.212862 0.262475 0.000000 4 6 0 0.000000 0.980640 0.000000 5 6 0 1.217594 0.269044 0.000000 6 1 0 2.085821 -1.708697 0.000000 7 1 0 -2.170018 0.770665 0.000000 8 1 0 2.157159 0.806111 0.000000 9 7 0 0.007867 -1.758344 0.000000 10 8 0 0.075510 2.297815 0.000000 11 1 0 -2.068124 -1.722321 0.000000 12 1 0 -0.793434 2.723904 0.000000 13 1 0 0.011127 -2.771424 0.000000 2.4H conjugate base (minus N–H proton)

285


frequencies

1 6 0 -1.191699 0.208196 0.000000 2 6 0 -1.118313 -1.180710 0.000000 3 6 0 1.152176 -1.157514 0.000000 4 6 0 1.204393 0.229547 0.000000 5 6 0 0.000000 0.933895 0.000000 6 1 0 -2.154726 0.710903 0.000000 7 1 0 -2.036224 -1.764432 0.000000 8 7 0 0.022046 -1.874362 0.000000 9 1 0 2.078409 -1.727569 0.000000 10 8 0 0.047736 2.287384 0.000000 11 1 0 -0.849867 2.638303 0.000000 12 1 0 2.146855 0.763770 0.000000 2.4H conjugate base (minus O–H proton) G4 enthalpy = -323.334212, S = 73.133, 3669.1 cm–1 N–H stretch, no imaginary

frequencies

1 6 0 0.000000 1.225339 0.305340 2 6 0 0.000000 1.190267 -1.046577 3 6 0 -0.000000 -1.190267 -1.046577 4 6 0 -0.000000 -1.225339 0.305340 5 6 0 0.000000 0.000000 1.112850 6 1 0 0.000000 2.175541 0.825313 7 1 0 0.000000 2.079515 -1.666058 8 7 0 0.000000 -0.000000 -1.726356 9 1 0 -0.000000 -2.079515 -1.666058 10 8 0 0.000000 0.000000 2.339442 11 1 0 -0.000000 -2.175541 0.825313 12 1 0 0.000000 -0.000000 -2.731816 2.2Me with 1 CH3CN B3LYP/6-31G(2df,p) = -496.034143, 2983.9 cm–1 O–H stretch, no imaginary frequencies 1 6 0 3.042051 0.119711 -0.000071 2 6 0 0.693904 -0.206948 0.000052 3 6 0 0.506209 1.184175 0.000070 4 6 0 1.602353 2.019047 0.000016 5 6 0 2.898927 1.480594 -0.000056 6 1 0 4.005330 -0.372149 -0.000126 7 1 0 -0.507082 1.563658 0.000126 8 1 0 1.460495 3.093961 0.000030 9 1 0 3.777445 2.111300 -0.000099 10 7 0 1.961196 -0.708088 -0.000019 11 8 0 -0.249862 -1.105483 0.000098 12 1 0 -1.178871 -0.714215 0.000147

286

13 6 0 2.138758 -2.174228 -0.000037 14 1 0 1.667545 -2.598203 0.887492 15 1 0 1.667449 -2.598193 -0.887520 16 1 0 3.204699 -2.392581 -0.000096 17 7 0 -2.730415 -0.176289 0.000049 18 6 0 -3.867155 0.009137 -0.000005 19 6 0 -5.300363 0.241968 -0.000078 20 1 0 -5.829537 -0.714917 -0.001837 21 1 0 -5.586358 0.806072 0.891718 22 1 0 -5.585791 0.809031 -0.890178

2.3Me with 1 CH3CN B3LYP/6-31G(2df,p) = -496.021372, 3214.6 cm–1 O–H stretch, no imaginary frequencies 1 6 0 -2.671827 1.210520 -0.005745 2 6 0 -1.404333 1.768168 0.000599 3 6 0 -0.281538 0.956303 0.001506 4 6 0 -0.436757 -0.443101 -0.003302 5 6 0 -1.741065 -0.950598 -0.009926 6 7 0 -2.808688 -0.130856 -0.011174 7 1 0 0.714543 1.383275 0.003931 8 1 0 -3.580900 1.794278 -0.006498 9 1 0 -1.308793 2.846737 0.002019 10 1 0 -1.926595 -2.016208 -0.014654 11 6 0 -4.159976 -0.733249 0.017429 12 1 0 -4.891510 0.018471 -0.273436 13 1 0 -4.194570 -1.566360 -0.684631 14 1 0 -4.375257 -1.088726 1.027127 15 8 0 0.547252 -1.318022 -0.004185 16 1 0 1.445147 -0.889486 -0.001593 17 6 0 5.594651 0.191605 0.003520 18 1 0 5.881499 0.760478 0.891907 19 1 0 6.121722 -0.766360 0.008984 20 1 0 5.884342 0.751892 -0.889389 21 6 0 4.160199 -0.037564 0.002320 22 7 0 3.022434 -0.220046 0.001361

2.4Me with 1 CH3CN B3LYP/6-31G(2df,p) = -496.031665, 3133.7 cm–1 O–H stretch, no imaginary frequencies 1 6 0 2.754162 0.870539 -0.008019 2 6 0 1.640359 -1.192903 -0.013752 3 6 0 0.417393 -0.576144 -0.006353 4 6 0 0.348588 0.836234 0.001237 5 6 0 1.568948 1.550360 -0.000083 6 1 0 3.711463 1.375772 -0.009250

287

7 1 0 -0.485021 -1.173374 -0.009820 8 1 0 1.557095 2.632453 0.001508 9 7 0 2.797226 -0.487441 -0.016385 10 6 0 4.098274 -1.180734 0.022364 11 1 0 3.978333 -2.189799 -0.370247 12 1 0 4.812819 -0.640264 -0.598905 13 1 0 4.465952 -1.228639 1.050123 14 8 0 -0.764512 1.515393 0.006225 15 1 0 1.740656 -2.270583 -0.018959 16 1 0 -1.583809 0.942557 0.005016 17 6 0 -5.513611 -0.711651 0.001358 18 1 0 -5.715204 -1.324965 0.883603 19 1 0 -6.170435 0.162369 0.017759 20 1 0 -5.722802 -1.297262 -0.897780 21 6 0 -4.126195 -0.281940 0.002093 22 7 0 -3.025863 0.059730 0.002682 PhOH B3LYP/6-31G(2df,p) = -307.492134, 3822.0 cm–1 O–H stretch, G4 enthalpy = -

307.293314, S = 74.495, no imaginary frequencies

1 6 0 -0.264028 1.196240 -0.000005 2 6 0 -0.939825 -0.025594 -0.000011 3 6 0 -0.220250 -1.221708 -0.000004 4 6 0 1.169742 -1.186985 0.000000 5 6 0 1.853274 0.028318 0.000001 6 6 0 1.128289 1.217061 0.000004 7 1 0 -0.827394 2.125862 0.000007 8 1 0 -0.763873 -2.159330 -0.000007 9 1 0 1.722996 -2.120614 -0.000002 10 1 0 2.937105 0.048027 0.000005 11 1 0 1.645499 2.171041 0.000007 12 8 0 -2.300808 -0.110857 0.000018 13 1 0 -2.671076 0.777868 -0.000073 PhO– G4 enthalpy = -306.739099, S = 73.826, no imaginary frequencies

1 6 0 0.285460 1.209739 -0.000001 2 6 0 1.085802 0.000310 0.000023 3 6 0 0.285090 -1.209627 0.000004

288

4 6 0 -1.099739 -1.197889 0.000001 5 6 0 -1.827999 0.000091 0.000002 6 6 0 -1.099752 1.197617 -0.000004 7 1 0 0.829092 2.153511 -0.000014 8 1 0 0.830029 -2.152648 -0.000003 9 1 0 -1.638295 -2.147703 -0.000003 10 1 0 -2.914443 -0.000018 -0.000002 11 1 0 -1.637956 2.147631 -0.000012 12 8 0 2.344800 -0.000277 -0.000015 PhOH with 1 CH3CN B3LYP/6-31G(2df,p) = -440.266662, 3657.8 cm–1 O–H stretch, G4 enthalpy = -511.749529, S = 88.183, no imaginary frequencies 1 6 0 -0.835094 0.733533 -0.000065 2 6 0 -1.030638 -0.652679 -0.000028 3 6 0 -2.334088 -1.162189 0.000036 4 6 0 -3.420274 -0.295790 0.000066 5 6 0 -3.230712 1.086114 0.000032 6 6 0 -1.932673 1.590198 -0.000033 7 1 0 0.175031 1.130138 -0.000121 8 1 0 -2.468837 -2.238116 0.000062 9 1 0 -4.425796 -0.705213 0.000116 10 1 0 -4.081732 1.758021 0.000056 11 1 0 -1.766825 2.663289 -0.000062 12 8 0 -0.009033 -1.540046 -0.000055 13 1 0 0.844586 -1.076614 -0.000067 14 6 0 5.138282 0.505371 0.000051 15 1 0 5.328477 1.128539 0.877838 16 1 0 5.816784 -0.351500 0.022282 17 1 0 5.340601 1.092038 -0.899898 18 6 0 3.756936 0.048719 0.000007 19 7 0 2.662791 -0.314269 -0.000023 4-O2NC6H4OH B3LYP/6-31G(2df,p) = -512.011439, 3815.8 cm–1 O–H stretch, no imaginary frequencies

289

1 6 0 -1.381927 -1.200734 -0.000066 2 6 0 -2.074034 0.016226 0.000007 3 6 0 -1.370520 1.226855 -0.000051 4 6 0 0.013562 1.219487 -0.000181 5 6 0 0.689353 0.000786 -0.000258 6 6 0 0.004547 -1.209860 -0.000196 7 1 0 -1.931868 -2.137483 -0.000022 8 1 0 -1.928101 2.155679 0.000008 9 1 0 0.584380 2.138159 -0.000229 10 1 0 0.565838 -2.134324 -0.000256 11 8 0 -3.425545 0.085336 0.000133 12 1 0 -3.796523 -0.803879 0.000173 13 7 0 2.152256 -0.007216 -0.000406 14 8 0 2.728190 1.075201 0.000416 15 8 0 2.716681 -1.096062 0.000405 4-O2NC6H4O– G4 enthalpy = -511.229221, S = 86.878, no imaginary frequencies

1 6 0 -1.418707 1.223141 -0.000116 2 6 0 -2.213246 0.000062 -0.000241 3 6 0 -1.418666 -1.223121 -0.000165 4 6 0 -0.050488 -1.219025 -0.000015 5 6 0 0.664949 0.000005 0.000080 6 6 0 -0.050485 1.218961 0.000033 7 1 0 -1.970852 2.159437 -0.000150 8 1 0 -1.971006 -2.159295 -0.000235 9 1 0 0.521473 -2.139538 0.000031 10 1 0 0.521411 2.139514 0.000115 11 8 0 -3.459711 -0.000043 -0.000385 12 7 0 2.076211 0.000003 0.000215 13 8 0 2.685194 -1.089652 0.000252 14 8 0 2.685187 1.089659 0.000293

290

4-O2NC6H4OH with 1 CH3CN B3LYP/6-31G(2df,p) = -644.789771, 3576.2 cm–1 O–H stretch, no imaginary frequencies 1 6 0 0.236375 -0.264822 -0.000510 2 6 0 0.310644 1.138402 -0.000239 3 6 0 -0.872620 1.894994 0.000160 4 6 0 -2.103271 1.265119 0.000297 5 6 0 -2.158389 -0.128588 0.000017 6 6 0 -0.996281 -0.895905 -0.000391 7 1 0 1.150341 -0.847894 -0.000824 8 1 0 -0.795699 2.975810 0.000369 9 1 0 -3.026988 1.827873 0.000607 10 1 0 -1.079143 -1.974412 -0.000594 11 8 0 1.473233 1.805848 -0.000347 12 1 0 2.232231 1.192951 -0.000619 13 6 0 6.059824 -1.182761 0.000410 14 1 0 6.894665 -0.477017 -0.002481 15 1 0 6.131988 -1.812103 0.891301 16 1 0 6.129720 -1.816699 -0.887399 17 6 0 4.797397 -0.460548 0.000154 18 7 0 3.797453 0.112508 -0.000049 19 7 0 -3.455360 -0.795341 0.000153 20 8 0 -4.462342 -0.092743 0.000455 21 8 0 -3.470122 -2.023609 -0.000167 2.5H with 1 CH3CN B3LYP/6-31G(2df,p) = -381.477048, 2955.2 cm–1 O–H stretch, no imaginary frequencies 1 6 0 -1.202691 1.178475 -0.000107 2 6 0 -2.584886 1.206895 0.000124 3 6 0 -3.283170 -0.000520 0.000237 4 6 0 -2.584080 -1.207469 0.000123 5 6 0 -1.201904 -1.178124 -0.000107 6 7 0 -0.555640 0.000392 -0.000219 7 1 0 -4.367454 -0.000882 0.000417 8 1 0 -0.582932 2.066076 -0.000197 9 1 0 -3.100864 2.158381 0.000214 10 1 0 -3.099422 -2.159300 0.000213 11 1 0 -0.581543 -2.065305 -0.000198 12 1 0 0.493825 0.000701 -0.000392 13 6 0 4.822609 -0.000450 0.000454 14 1 0 5.194957 0.993174 -0.263177

291

15 1 0 5.194226 -0.269036 0.992992 16 1 0 5.194524 -0.725393 -0.728614 17 6 0 3.370347 0.000205 -0.000101 18 7 0 2.218116 0.000680 -0.000494 2.2H with 1 CH3CN associated with NH B3LYP/6-31G(2df,p) = -456.711770, 3802.3 and 2945.3 cm–1 O–H and N–H stretches, respectively; no imaginary frequencies 1 6 0 -1.006586 -1.420620 -0.000009 2 6 0 -1.252059 0.930091 -0.000001 3 6 0 -2.642262 0.800531 0.000014 4 6 0 -3.191261 -0.470437 0.000018 5 6 0 -2.367227 -1.605109 0.000006 6 1 0 -0.284383 -2.226825 -0.000019 7 1 0 -3.264409 1.687453 0.000023 8 1 0 -4.269614 -0.584353 0.000030 9 1 0 -2.780102 -2.604597 0.000009 10 7 0 -0.483681 -0.173888 -0.000012 11 8 0 -0.566522 2.063847 -0.000007 12 1 0 -1.151046 2.832900 0.000000 13 1 0 0.562069 -0.074000 -0.000027 14 6 0 4.895022 -0.154224 0.000036 15 1 0 5.273982 -0.662867 0.890518 16 1 0 5.274042 -0.663068 -0.890307 17 1 0 5.253703 0.878594 -0.000069 18 6 0 3.442640 -0.172459 -0.000012 19 7 0 2.290587 -0.189062 -0.000047 2.2H with 1 CH3CN associated with NH and OH B3LYP/6-31G(2df,p) = -456.713966, 3514.0 and 3292.9 cm–1 N–H (symmetric, a little coupling to O–H) and O–H (asymmetric, a little coupling to N–H) stretches, respectively; no imaginary frequencies 1 6 0 -1.674563 1.538240 -0.000001 2 6 0 -0.943649 -0.738624 -0.000000 3 6 0 -2.279191 -1.165163 0.000001 4 6 0 -3.284449 -0.222699 0.000001 5 6 0 -2.986072 1.154940 0.000001 6 1 0 -1.339848 2.566924 -0.000001 7 1 0 -2.472290 -2.229720 0.000001 8 1 0 -4.319222 -0.546924 0.000002 9 1 0 -3.767753 1.902205 0.000001 10 7 0 -0.692679 0.594228 -0.000001 11 8 0 0.044055 -1.592979 -0.000001

292

12 1 0 0.927363 -1.143721 -0.000001 13 1 0 0.284114 0.880142 -0.000002 14 6 0 4.894370 0.362329 0.000001 15 1 0 5.423335 -0.595052 0.000013 16 1 0 5.179039 0.927258 -0.891811 17 1 0 5.179035 0.927277 0.891804 18 6 0 3.462536 0.126283 -0.000000 19 7 0 2.324093 -0.062284 -0.000001 2.2H with 1 CH3CN associated with OH B3LYP/6-31G(2df,p) = -456.716860, 3568.1 and 2922.8 cm–1 N–H and O–H stretches, respectively; no imaginary frequencies 1 6 0 3.261139 -0.460471 -0.000117 2 6 0 0.865731 -0.523792 0.000047 3 6 0 0.835198 0.881041 0.000100 4 6 0 2.025340 1.578378 0.000044 5 6 0 3.263280 0.906964 -0.000066 6 1 0 4.153280 -1.072356 -0.000200 7 1 0 -0.124857 1.379595 0.000185 8 1 0 2.005337 2.662723 0.000087 9 1 0 4.200026 1.446977 -0.000110 10 7 0 2.079124 -1.130917 -0.000061 11 8 0 -0.146390 -1.336328 0.000094 12 1 0 -1.044633 -0.870839 0.000159 13 1 0 2.071158 -2.145837 -0.000099 14 6 0 -3.645460 0.067153 0.000067 15 7 0 -2.526598 -0.205685 0.000131 16 6 0 -5.056134 0.410232 -0.000167 17 1 0 -5.657428 -0.503045 -0.002508 18 1 0 -5.297615 0.994418 0.891896 19 1 0 -5.296404 0.998171 -0.890091 2.3H with 1 CH3CN associated with NH B3LYP/6-31G(2df,p) = -456.704813, 3803.5 and 2957.4 cm–1 symmetric and asymmetric O–H and N–H stretches, respectively; no imaginary frequencies 1 6 0 0.686597 1.548131 -0.000047 2 6 0 2.062382 1.702461 0.000133 3 6 0 2.879977 0.578533 0.000174 4 6 0 2.309102 -0.701066 0.000045 5 6 0 0.917361 -0.801091 -0.000121 6 7 0 0.169300 0.309210 -0.000167 7 1 0 3.959911 0.690779 0.000318 8 1 0 -0.017006 2.369123 -0.000088

293

9 1 0 2.489704 2.696999 0.000248 10 1 0 0.406038 -1.754574 -0.000191 11 8 0 2.993851 -1.849050 0.000060 12 1 0 -0.874218 0.197735 -0.000336 13 1 0 3.947068 -1.696963 0.000221 14 6 0 -5.173836 -0.314577 0.000506 15 1 0 -5.652141 0.545754 -0.475357 16 1 0 -5.439706 -1.220302 -0.551191 17 1 0 -5.537695 -0.402428 1.027748 18 6 0 -3.731924 -0.141142 -0.000127 19 7 0 -2.587974 -0.003670 -0.000581 2.3H with 1 CH3CN associated with OH B3LYP/6-31G(2df,p) = -456.703181, 3572.7 and 3179.8 cm–1 N–H and O–H stretches, respectively; no imaginary frequencies 1 6 0 3.210068 0.950146 -0.000000 2 6 0 1.974121 1.573187 0.000000 3 6 0 0.811321 0.815107 0.000001 4 6 0 0.877752 -0.593559 0.000000 5 6 0 2.150571 -1.178115 -0.000001 6 7 0 3.242905 -0.395854 -0.000001 7 1 0 -0.159773 1.296929 0.000001 8 1 0 4.159134 1.466663 -0.000001 9 1 0 1.928799 2.654874 0.000001 10 1 0 2.292886 -2.250068 -0.000001 11 8 0 -0.158107 -1.402863 0.000001 12 1 0 4.148047 -0.854020 -0.000001 13 1 0 -1.030188 -0.920106 0.000001 14 6 0 -5.097768 0.396749 -0.000001 15 1 0 -5.353318 0.976812 -0.890721 16 1 0 -5.678182 -0.529915 -0.000086 17 1 0 -5.353350 0.976669 0.890803 18 6 0 -3.678818 0.086398 0.000000 19 7 0 -2.553289 -0.160489 0.000001 2.4H with 1 CH3CN associated with NH B3LYP/6-31G(2df,p) = -456.713702, 3784.3 and 3029.7 cm–1 O–H and N–H stretches, respectively; no imaginary frequencies 1 6 0 0.692840 -1.174373 -0.000183 2 6 0 0.705736 1.176588 -0.000274 3 6 0 2.079961 1.205101 0.000063 4 6 0 2.785463 -0.011938 0.000281

294

5 6 0 2.063462 -1.219930 0.000157 6 1 0 0.074347 -2.062707 -0.000284 7 1 0 2.597696 2.157058 0.000158 8 1 0 2.590713 -2.164739 0.000331 9 7 0 0.040349 0.006899 -0.000397 10 8 0 4.108128 -0.097271 0.000607 11 1 0 0.100304 2.074027 -0.000446 12 1 0 4.530807 0.772059 0.000671 13 1 0 -1.003839 0.012764 -0.000668 14 6 0 -5.356076 -0.003965 0.000514 15 1 0 -5.722965 -0.829269 -0.615640 16 1 0 -5.727243 -0.128387 1.021344 17 1 0 -5.735032 0.938294 -0.404383 18 6 0 -3.903602 0.005974 -0.000205 19 7 0 -2.751281 0.013719 -0.000756 2.4H with 1 CH3CN associated with OH B3LYP/6-31G(2df,p) = -456.714969, 3606.6 and 3086.8 cm–1 N–H and O–H stretches, respectively; no imaginary frequencies 1 6 0 3.277642 -0.450189 -0.000225 2 6 0 1.971611 1.525843 0.000064 3 6 0 0.812021 0.800250 0.000187 4 6 0 0.876970 -0.616328 0.000100 5 6 0 2.155367 -1.227929 -0.000111 6 1 0 4.280686 -0.856220 -0.000388 7 1 0 -0.143804 1.307295 0.000348 8 1 0 2.230257 -2.307331 -0.000180 9 7 0 3.173548 0.902557 -0.000137 10 8 0 -0.169631 -1.389229 0.000204 11 1 0 1.990583 2.607943 0.000120 12 1 0 -1.040782 -0.893239 0.000354 13 1 0 4.017167 1.460684 -0.000225 14 6 0 -3.671335 0.090937 -0.000002 15 7 0 -2.545576 -0.154060 0.000141 16 6 0 -5.090620 0.398731 -0.000181 17 1 0 -5.668970 -0.529226 -0.000067 18 1 0 -5.346994 0.978433 0.890565 19 1 0 -5.346838 0.978116 -0.891179

2.2H with 2 CH3CN B3LYP/6-31G(2df,p) = -589.508739, 3125.5 and 3092.6 cm–1 symmetric and asymmetric O–H and N–H stretches, respectively; no imaginary frequencies 1 6 0 1.604141 2.173424 -0.000006 2 6 0 -0.232833 0.665153 0.000047 3 6 0 -1.123036 1.752244 -0.000001 4 6 0 -0.614836 3.035350 -0.000050

295

5 6 0 0.772385 3.262245 -0.000053 6 1 0 2.684761 2.233366 -0.000008 7 1 0 -2.186727 1.555247 0.000001 8 1 0 -1.297474 3.878113 -0.000087 9 1 0 1.183579 4.262209 -0.000092 10 7 0 1.093932 0.919945 0.000043 11 8 0 -0.551237 -0.600185 0.000097 12 1 0 -1.540083 -0.754113 0.000081 13 1 0 1.761277 0.121205 0.000075 14 6 0 5.089726 -2.749152 -0.000098 15 1 0 5.677421 -2.667269 -0.918270 16 1 0 5.747566 -2.592417 0.858865 17 1 0 4.661033 -3.753096 0.059161 18 6 0 4.028171 -1.756836 -0.000001 19 7 0 3.188087 -0.968019 0.000080 20 6 0 -5.612762 -2.035284 -0.000063 21 1 0 -6.145570 -1.693548 -0.891410 22 1 0 -5.585171 -3.128302 0.001235 23 1 0 -6.146456 -1.691456 0.889949 24 7 0 -3.184578 -1.093720 0.000036 25 6 0 -4.258679 -1.509796 -0.000008

3H with 2 CH3CN B3LYP/6-31G(2df,p) = -589.498268, 3283.2 and 3061.0 cm–1 O–H (a little coupling to N–H, symmetric) and N–H (a little coupling to O–H, asymmetric) stretches, respectively; no imaginary frequencies 1 6 0 1.235729 1.779695 0.000040 2 6 0 -0.103459 2.131792 -0.000139 3 6 0 -1.079263 1.144021 -0.000051 4 6 0 -0.710444 -0.214355 0.000213 5 6 0 0.657823 -0.510546 0.000382 6 7 0 1.562146 0.477146 0.000297 7 1 0 -2.130895 1.407000 -0.000187 8 1 0 2.053330 2.486676 -0.000024 9 1 0 -0.378061 3.179028 -0.000347 10 1 0 1.024928 -1.528049 0.000571 11 8 0 -1.553455 -1.230639 0.000312 12 1 0 2.571487 0.214429 0.000436 13 1 0 -2.500830 -0.939473 0.000173 14 6 0 6.785988 -0.936997 -0.000733 15 1 0 7.368402 -0.229811 0.595864 16 1 0 6.895894 -1.937506 0.426081 17 1 0 7.170877 -0.941890 -1.023984 18 6 0 5.385783 -0.549807 -0.000040 19 7 0 4.275220 -0.242674 0.000480 20 6 0 -6.789767 -0.460527 -0.000323 21 1 0 -7.155139 0.058193 -0.890548 22 1 0 -7.176719 -1.483115 -0.000925 23 1 0 -7.155330 0.057219 0.890389 24 6 0 -5.337031 -0.484584 -0.000179

296

25 7 0 -4.184860 -0.504435 -0.000065

4H with 2 CH3CN B3LYP/6-31G(2df,p) = -589.508368, 3209.6 and 3139.7 cm–1 symmetric and asymmetric O–H and N–H stretches, respectively, no imaginary frequencies 1 6 0 1.305857 1.621531 -0.000101 2 6 0 0.615582 -0.626829 -0.000473 3 6 0 -0.706084 -0.261870 -0.000248 4 6 0 -1.042655 1.112149 0.000061 5 6 0 0.008539 2.057324 0.000135 6 1 0 2.153946 2.294110 -0.000046 7 1 0 -1.479950 -1.018060 -0.000305 8 1 0 -0.223429 3.114059 0.000380 9 7 0 1.593878 0.301356 -0.000405 10 8 0 -2.271448 1.560325 0.000291 11 1 0 0.939092 -1.659950 -0.000704 12 1 0 -2.955739 0.837126 0.000228 13 1 0 2.585805 -0.001391 -0.000582 14 6 0 6.823009 -1.177094 0.000788 15 1 0 7.398315 -0.480862 -0.615254 16 1 0 7.214554 -1.156694 1.021305 17 1 0 6.936152 -2.186416 -0.403780 18 6 0 5.420570 -0.797053 -0.000014 19 7 0 4.308290 -0.495574 -0.000616 20 6 0 -6.494521 -1.587082 0.000124 21 1 0 -6.574614 -2.216079 0.890645 22 1 0 -7.314875 -0.864246 0.000315 23 1 0 -6.574777 -2.215794 -0.890583 24 6 0 -5.222306 -0.885726 0.000122 25 7 0 -4.213716 -0.328713 0.000119

Sensor 2.1 • phenol complexed at carbonyl oxygen B3LYP/cc-pVDZ = -1049.033192, zpe = 0.324841, thermal correction to the enthalpy = 0.342525, no imaginary frequencies, B3LYP/cc-pVTZ//B3LYP/cc-pVDZ = -1049.332415, M06-2X/cc-pVDZ = -1048.645252, zpe = 0.328495, thermal correction to the enthalpy = 0.346093, no imaginary frequencies,M06-2X/cc-pVTZ//M06-2X/cc-pVDZ = -1048.907495 B3LYP geometry: 1 6 0 -1.514343 2.079211 -0.206216 2 6 0 -1.438882 3.423462 -0.449822 3 6 0 0.847834 3.417120 0.241025 4 6 0 0.816656 2.089312 0.495552 5 6 0 -0.693587 0.061694 0.443600 6 6 0 -2.109489 0.024858 0.024607 7 1 0 -2.302788 3.972747 -0.819210

297

8 1 0 1.747799 4.008836 0.392835 9 1 0 1.672761 1.523129 0.864602 10 6 0 -2.966052 -1.160974 0.004944 11 6 0 -2.498024 -2.415151 0.448210 12 6 0 -4.291931 -1.053509 -0.465750 13 6 0 -3.341022 -3.527680 0.418680 14 1 0 -1.475450 -2.499675 0.814295 15 6 0 -5.124381 -2.169030 -0.492874 16 1 0 -4.648027 -0.080712 -0.806655 17 6 0 -4.652648 -3.411992 -0.050620 18 1 0 -2.968089 -4.494001 0.765892 19 1 0 -6.148698 -2.072514 -0.860593 20 1 0 -5.307448 -4.286325 -0.072397 21 8 0 0.075088 -0.834380 0.850559 22 6 0 -0.187828 5.547125 -0.441155 23 1 0 -0.073361 6.075956 0.520286 24 1 0 0.671619 5.793203 -1.084484 25 1 0 -1.103531 5.900879 -0.931245 26 7 0 -2.551000 1.231057 -0.351704 27 7 0 -0.272900 4.106424 -0.239596 28 7 0 -0.366887 1.393410 0.278682 29 1 0 1.727647 -0.649953 1.260456 30 8 0 2.670983 -0.391906 1.429629 31 6 0 3.493734 -1.015052 0.541951 32 6 0 3.011407 -1.859920 -0.471815 33 6 0 4.874802 -0.790395 0.657217 34 6 0 3.908614 -2.467999 -1.353698 35 1 0 1.936037 -2.030518 -0.555907 36 6 0 5.758994 -1.402825 -0.231735 37 1 0 5.232933 -0.135596 1.454522 38 6 0 5.284650 -2.245148 -1.243976 39 1 0 3.522355 -3.124702 -2.137656 40 1 0 6.832199 -1.221344 -0.130142 41 1 0 5.979960 -2.723990 -1.936535 M06-2X geometry: 1 6 0 0.911573 2.156679 0.161582 2 6 0 0.464587 3.417987 0.415824 3 6 0 -1.677597 2.824362 -0.435403 4 6 0 -1.280940 1.565357 -0.701127 5 6 0 0.694847 0.019660 -0.546678 6 6 0 2.041451 0.350150 -0.034336

298

7 1 0 1.125268 4.163996 0.852907 8 1 0 -2.688358 3.163528 -0.648055 9 1 0 -1.919787 0.808329 -1.156035 10 6 0 3.173683 -0.576811 0.036205 11 6 0 3.062957 -1.898114 -0.421958 12 6 0 4.393189 -0.131093 0.571205 13 6 0 4.160152 -2.753342 -0.343344 14 1 0 2.116242 -2.240582 -0.837242 15 6 0 5.481111 -0.991241 0.646161 16 1 0 4.464184 0.898279 0.922808 17 6 0 5.368274 -2.306279 0.188441 18 1 0 4.068099 -3.778997 -0.702631 19 1 0 6.424952 -0.636378 1.062422 20 1 0 6.223699 -2.980738 0.246477 21 8 0 0.218360 -1.034901 -0.999387 22 6 0 -1.329776 5.096231 0.425586 23 1 0 -1.743062 5.557031 -0.482937 24 1 0 -2.116469 5.043558 1.192655 25 1 0 -0.511059 5.721715 0.797684 26 7 0 2.126572 1.608992 0.370319 27 7 0 -0.816800 3.770123 0.127348 28 7 0 0.027756 1.203954 -0.400888 29 1 0 -1.401957 -1.287972 -1.518381 30 8 0 -2.367364 -1.271321 -1.726359 31 6 0 -3.069559 -1.642725 -0.628523 32 6 0 -2.449879 -1.997199 0.576252 33 6 0 -4.466175 -1.649850 -0.718405 34 6 0 -3.230667 -2.352421 1.674923 35 1 0 -1.359920 -1.999275 0.630274 36 6 0 -5.232163 -2.007150 0.386620 37 1 0 -4.926297 -1.376787 -1.668869 38 6 0 -4.622056 -2.358416 1.591949 39 1 0 -2.738202 -2.630189 2.608534 40 1 0 -6.320415 -2.012822 0.303867 41 1 0 -5.225640 -2.639110 2.455188 Sensor 2.1 • phenol complexed at -nitrogen

299

B3LYP/cc-pVDZ = -1049.028450, zpe = 0.324435, thermal correction to the enthalpy = 0.342206, no imaginary frequencies, B3LYP/cc-pVTZ//B3LYP/cc-pVDZ = -1049.328732, M06-2X/cc-pVDZ = -1048.641921, zpe = 0.3284070, thermal correction to the enthalpy = 0.345756, no imaginary frequencies, M06-2X/cc-pVTZ//M06-2X/cc-pVDZ = -1048.904974 B3LYP geometry: 1 6 0 -0.390781 1.626584 0.228653 2 6 0 0.665441 2.468284 0.441833 3 6 0 -0.676770 4.302111 -0.313945 4 6 0 -1.735810 3.490384 -0.530886 5 6 0 -2.531424 1.095225 -0.389606 6 6 0 -1.733569 -0.069124 0.076178 7 1 0 1.610692 2.091195 0.830190 8 1 0 -0.717379 5.371819 -0.507105 9 1 0 -2.699359 3.827766 -0.908026 10 6 0 -2.218183 -1.443808 0.161822 11 6 0 -3.520308 -1.773566 -0.271795 12 6 0 -1.393414 -2.465304 0.681516 13 6 0 -3.973954 -3.090734 -0.189976 14 1 0 -4.158517 -0.983527 -0.666990 15 6 0 -1.855788 -3.776285 0.758676 16 1 0 -0.389670 -2.219640 1.029630 17 6 0 -3.147986 -4.095800 0.322182 18 1 0 -4.983394 -3.333485 -0.529845 19 1 0 -1.205616 -4.555299 1.163082 20 1 0 -3.508213 -5.125360 0.383979 21 8 0 -3.686315 1.218893 -0.795512 22 6 0 1.649671 4.728131 0.387364 23 1 0 1.940988 5.212564 -0.559454 24 1 0 1.374767 5.509943 1.114674 25 1 0 2.512164 4.173627 0.777070 26 7 0 -0.489049 0.289983 0.421949 27 7 0 0.541416 3.806526 0.176798 28 7 0 -1.612297 2.136268 -0.262589 29 1 0 1.138308 -0.327627 0.994841 30 8 0 2.064569 -0.351210 1.344815 31 6 0 2.902716 -0.965714 0.464594 32 6 0 2.474674 -1.462730 -0.777722 33 6 0 4.251748 -1.094800 0.832124 34 6 0 3.391092 -2.080656 -1.633291 35 1 0 1.426297 -1.363800 -1.067211 36 6 0 5.156361 -1.711936 -0.032287

300

37 1 0 4.566743 -0.707782 1.803501 38 6 0 4.734969 -2.209356 -1.271041 39 1 0 3.044785 -2.465431 -2.595935 40 1 0 6.203166 -1.807609 0.267456 41 1 0 5.445598 -2.693682 -1.943742 M06-2X geometry: 1 6 0 -0.339348 1.377930 -0.384831 2 6 0 -1.655827 1.576256 -0.671163 3 6 0 -1.511603 3.746267 0.311119 4 6 0 -0.208486 3.578633 0.604077 5 6 0 1.700087 1.946570 0.464976 6 6 0 1.648092 0.582039 -0.125294 7 1 0 -2.239581 0.807983 -1.177822 8 1 0 -2.047691 4.659675 0.556144 9 1 0 0.412832 4.320546 1.100378 10 6 0 2.759549 -0.367050 -0.159939 11 6 0 4.019730 -0.005869 0.341474 12 6 0 2.570219 -1.653826 -0.691750 13 6 0 5.068236 -0.921918 0.306197 14 1 0 4.157348 0.992047 0.756258 15 6 0 3.621890 -2.560470 -0.720896 16 1 0 1.589787 -1.934360 -1.079605 17 6 0 4.875343 -2.197072 -0.222576 18 1 0 6.045530 -0.634750 0.696250 19 1 0 3.465656 -3.557138 -1.135232 20 1 0 5.700313 -2.910403 -0.247271 21 8 0 2.588454 2.590654 1.006259 22 6 0 -3.656444 2.996444 -0.628905 23 1 0 -4.197137 3.284664 0.283819 24 1 0 -3.759343 3.797056 -1.376846 25 1 0 -4.102389 2.077716 -1.025138 26 7 0 0.447360 0.298496 -0.609747 27 7 0 -2.258061 2.747581 -0.326101 28 7 0 0.405035 2.382762 0.262083 29 1 0 -0.643873 -0.991817 -1.306984 30 8 0 -1.479508 -1.417810 -1.608450 31 6 0 -2.112393 -1.976061 -0.545914 32 6 0 -1.538201 -2.037780 0.729856 33 6 0 -3.394343 -2.497254 -0.754422 34 6 0 -2.248292 -2.618410 1.779217 35 1 0 -0.535934 -1.636318 0.889967

301

36 6 0 -4.090886 -3.075222 0.302247 37 1 0 -3.818122 -2.443566 -1.758014 38 6 0 -3.525504 -3.138266 1.576662 39 1 0 -1.790084 -2.666417 2.768475 40 1 0 -5.087638 -3.483921 0.127292 41 1 0 -4.072481 -3.595289 2.401411

302


Enantiopurity of commercial samples. The optical rotation reported by Sigma-Aldrich

was (S)-3.1: [ɑ]D20 = +58.4° (c 2.0, ethanol), and its enantiopurity was given to be 99.0 %

ee (58.4/59 100). For the (R)-enantiomer supplied by Ark Pharm, Inc., its optical rotation

was given at a different concentration (c 1.0, ethanol) and the temperature of the

measurement was not supplied. Consequently, we determined its enantiopurity by

measuring its rotation under the same conditions as the S sample. The results are as

follows, where the uncertainties are given as 2σ: (S)-3.1 [ɑ]D25.2 = +57.39 ± 0.08° (c 2.0,

ethanol) and (R)-3.1 [ɑ]D25.4 = -57.14 ± 0.24° (c 2.0, ethanol). From our rotations at 25.3 ±

0.1 °C, the (R)-ibuprofen was found to be 99.6 ± 0.4% as enantiopure as the (S)- sample

and was found to be 98.6 ± 0.5% ee.

To assess the ees of both enantiomers of ibuprofen further, these quantities were

taken as variables and fit using the HPLC data with the best resolution (1% overlap)

collected at 220 nm for all of the standards listed in Tables 1 and 3. That is, the sum of

the squares of the errors (i.e., observed – calculated ees) were minimized as a function of

the ees of both (R)- and (S)-ibuprofen. When no constraints were used in this process, the

enantiopurities of both commercial samples were determined to be 98.7% ee. If the

enantiopurity of the (R)-sample was constrained to 99.6% as pure as the (S)-enantiomer,

then the resulting ees were found to be 98.5% (R) and 98.9% (S). In both cases, these

results are in excellent accord with the optical rotation data.

303

Calibration curves for micropipettes and calculated ees for all standards. The 20 -

200 μL and 100 - 1000 μL micropipettes were calibrated by dispensing a range of volumes

of HPLC grade hexanes into tared vials. The masses were then converted to volumes

using the density of hexanes (d = 0.6594 g mL-1 at 20 °C) and the data were linearly fit as

shown in Figure S1. Corrected volumes were obtained from the trendlines and used, along

with the ees of the commercial samples and their chemical purities, to determine the

enantiopurities of each prepared standard (Table S1).

y = 1.0089x - 1.1898R² = 0.9999

0

55

110

165

220

0 55 110 165 220

Vo

lum

e D

isp

ense

d (μ

L)

Pipette Setting (μL)

304

Figure S1. Calibration curves for the 20 – 200 μL (top) and 100 – 1000 μL (bottom)

micropipettes.

y = 0.9948x + 4.0137R² = 0.9998

0

100

200

300

400

500

600

700

800

900

1000

0 100 200 300 400 500 600 700 800 900 1000

Vo

lum

e D

isp

ense

d (μ

L)

Pipette Setting (μL)

305

Table S1. Volumes used to make each standard and its corresponding calculated enantiopurity.

aVolumes ≤ 200 μL and > 200 μL were dispensed with the 20 - 200 μL and 100 – 1000 μL micropipettes, respectively. bVolumes were corrected using the linear calibration equations in Figure S1. cCalculated using the corrected volumes of the stock solutions (1 mg mL–1), the ees of the commercial samples (99.0% (S) and 98.6% (R)) and their chemical

purities (100% and 99.5% for (S) and (R)-ibuprofen).

major enantiomer

pipette setting for (R)-stock

solution (μL)a

pipette setting for (S)-stock

solution (μL)a

corrected (R)-volume

(μL)b

corrected (S)-volume

(μL)b

(R)-3.1 (mg)c

(S)-3.1 (mg)c calc %(R) calc %(S)

calc ee (%)

R

1000 0 998.9 0.0 9.92 0.07 99.3 0.7 98.6

990 10 989.0 8.9 9.82 0.16 98.4 1.6 96.8

980 20 979.0 19.0 9.72 0.26 97.4 2.6 94.8

970 30 969.1 29.1 9.62 0.36 96.4 3.6 92.8

960 40 959.1 39.2 9.52 0.46 95.4 4.6 90.8

950 50 949.2 49.3 9.43 0.56 94.4 5.6 88.8

900 100 899.4 99.7 8.93 1.06 89.4 10.6 78.8

800 200 799.9 200.6 7.95 2.05 79.5 20.5 58.8

700 300 700.4 302.5 6.97 3.06 69.5 30.5 38.8

600 400 601.0 401.9 5.99 4.04 59.7 40.3 19.2

S

500 500 501.5 501.4 5.00 5.02 49.9 50.1 0.4

400 600 402.0 600.9 4.02 6.01 40.1 59.9 20.0

300 700 302.5 700.4 3.04 6.99 30.3 69.7 39.6

200 800 200.6 799.9 2.03 7.97 20.3 79.7 59.6

100 900 99.7 899.3 1.04 8.95 10.4 89.6 79.4

50 950 49.3 949.1 0.54 9.45 5.4 94.6 89.2

40 960 39.2 959.0 0.44 9.54 4.4 95.6 91.2

30 970 29.1 969.0 0.34 9.64 3.4 96.6 93.2

20 980 19.0 978.9 0.24 9.74 2.4 97.6 95.2

10 990 8.9 988.9 0.14 9.84 1.4 98.6 97.2

0 1000 0.0 998.8 0.05 9.94 0.5 99.5 99.0

306

Integration parameters and employed values. A brief explanation for each parameter

used in the analyses is provided. For more specific details, see the OpenLAB CDS Data

Analysis and Reference Guide. All of these quantities can be edited post data collection.

Tangent skim mode – New exponential: This is the standard model used for tangent

skimming where the instrument uses an exponential equation to correct the integration of

asymmetric peaks. This uses the tail or front skim ratio and skim valley ratio parameters

to correct for asymmetric peaks.

Tail skim height ratio – 0.00: Value used to initiate tail skimming. When set to 0, tail

skimming is turned off.

Front skim height ratio – 0.00: Value used to initiate front skimming. When set to 0, front

skimming is turned off.

Skim valley ratio – 0.00: Parameter used for both tail and front skimming. When set to 0,

neither correction is used.

Baseline correction – Advanced: This is the standard baseline correction mode.

Peak to valley ratio – 500.00: Value used to decide whether two intersecting peaks

should be separated by a vertical drop method or a valley drop method; the latter

generates a new baseline under the peaks. In all chromatograms for this study, the

standard value of 500 separated all peaks by the vertical drop method.

Peak width – 0.2 min: This value helps with peak identification and it is recommended to

set the value less than or equal to the width of the narrowest peak of interest.

Integration off – 0.000 min: The integrator does not integrate the chromatogram until an

“Integration ON” time has been reached.

307

Integration on – 4.200 min: Chromatogram is integrated until the end of the run or until

an “Integration OFF” time is reached. For the poorest peak separation studied (i.e., 17%

overlap), this value was changed to 3.800 min due to the smaller retention times of the

two enantiomers.

Reference wavelength – 360 nm: The absorbance at the monitored wavelength is

subtracted by the absorbance at the reference wavelength; 360 nm is the standard value

and was used in this study. This prevents baseline drift and helps detect all absorbing

components in an analysis. The sample must not absorb at this wavelength.

Slope sensitivity. When determining a range of slope sensitivity values (s) for the most

enantiopure standards, a larger range (0.01 to 0.25) was acceptable when the major

enantiomer eluted second compared to the reverse elution order (0.01 – 0.10). The same

trend was observed with a lower ee standard (i.e., 20%), and s = 0.01 – 0.30 and 0.01 –

0.23, respectively were found to be satisfactory. This difference in s values can be

attributed to the observation that first peak in the chromatogram is sharper and narrower

than the second (see Figures S10-S60). When examining the slope sensitivity for the

commercial (R)-sample at 254 nm, it was found that s = 0.1 was only satisfactory in three

of the five runs; in the other two cases the minor enantiomer was not detected. Noise in

the baseline perturbs the valley between the two peaks (Figure S2) necessitating a smaller

value (0.01) for s. The resulting ees obtained with s = 0.01 are similar to those when a

tenfold larger value is used. This issue was not a problem at other wavelengths or with

other standards since the signal to noise ratio is better in these cases.

308

Figure S2. Enlarged chromatograms of the five injections for (R)-ibuprofen monitored at

254 nm. The black arrow represents the starting location of where the minor enantiomer

is detected when it is observed by the integrator.

0

0.05

0.1

0.15

0.2

0.25

0.3

5 5.5 6 6.5 7 7.5 8

Ab

sorb

ance

(m

AU

)

Time (min)

Trial 1 Trial 2 Trial 3 Trial 4 Trial 5

309

Data Summary Tables.

Table S2. Data collected at 254 nm with 1% overlap.

major enantiomer ee (%) error

(%)b 2σ (%)

range (%) calc obsa

R

98.6 98.8 0.2 0.6 0.8

96.8 96.6 -0.2 0.4 0.5

94.8 94.6 -0.2 0.6 0.7

92.8 92.2 -0.6 1.1 1.2

90.8 90.5 -0.3 1.1 1.3

88.8 88.6 -0.2 1.1 1.4

78.8 79.1 0.3 0.9 1.0

58.8 58.5 -0.3 1.0 1.3

38.8 39.5 0.7 1.1 1.3

19.2 20.7 1.5 0.6 0.8

S

0.4 -1.4 -1.8 0.4 0.5

20.0 17.7 -2.3 0.6 0.8

39.6 38.1 -1.5 0.5 0.6

59.6 57.4 -2.2 0.5 0.5

79.4 78.4 -1.0 0.3 0.4

89.2 89.3 0.1 0.3 0.3

91.2 91.2 0.0 0.3 0.4

93.2 93.3 0.1 0.3 0.3

95.2 95.5 0.3 0.3 0.3

97.2 97.3 0.1 0.4 0.5

99.0 99.4 0.4 0.4 0.4

aAverage of five injections. Negative number indicates excess of the opposite enantiomer. bobs – calc


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 99.0 0.4 0.2 0.3

96.8 96.6 -0.2 0.6 0.7

94.8 94.6 -0.2 0.4 0.4

92.8 92.8 0.0 0.3 0.3

90.8 90.8 0.0 0.3 0.4

88.8 88.8 0.0 0.8 1.0

78.8 78.8 0.0 2.0 2.3

58.8 57.9 -0.9 1.4 1.6

38.8 39.5 0.7 0.9 1.2

19.2 20.1 0.9 0.6 0.8

S

0.4 -1.0 -1.4 0.4 0.6

20.0 18.2 -1.8 0.5 0.5

39.6 38.5 -1.1 0.3 0.3

59.6 57.7 -1.9 0.3 0.4

79.4 78.7 -0.7 0.2 0.2

89.2 89.4 0.2 0.2 0.3

91.2 91.4 0.2 0.1 0.2

93.2 93.5 0.3 0.1 0.1

95.2 95.6 0.4 0.2 0.2

97.2 97.5 0.3 0.2 0.2

99.0 99.6 0.6 0.1 0.1

aAverage of five injections. Negative number indicates excess of the opposite enantiomer. bobs – calc.

310


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 98.8 0.2 0.6 0.7

96.8 96.4 -0.4 0.2 0.3

94.8 94.5 -0.3 0.3 0.4

92.8 92.7 -0.1 0.3 0.3

90.8 90.8 0.0 0.3 0.4

88.8 88.6 -0.2 0.4 0.5

78.8 78.8 0.0 1.9 2.2

58.8 57.8 -1.0 1.3 1.4

38.8 39.1 0.2 0.6 0.7

19.2 19.9 0.7 0.6 0.7

S

0.4 -0.9 -1.3 0.3 0.4

20.0 18.2 -1.8 0.4 0.5

39.6 38.4 -1.2 0.3 0.3

59.6 57.7 -1.9 0.2 0.3

79.4 78.6 -0.8 0.1 0.2

89.2 89.3 0.1 0.1 0.1

91.2 91.3 0.1 0.1 0.2

93.2 93.4 0.2 0.1 0.1

95.2 95.5 0.3 0.2 0.2

97.2 97.5 0.3 0.1 0.2

99.0 99.6 0.6 0.1 0.1



major enantiomer ee (%) error

(%)b 2σ (%)

range (%) calc obsa

R

98.6 98.7 0.1 0.7 0.8

96.8 96.5 -0.3 0.6 0.7

94.8 94.5 -0.3 0.3 0.4

92.8 92.7 -0.1 0.3 0.3

90.8 90.8 0.0 0.4 0.5

88.8 88.7 -0.1 0.8 0.9

78.8 78.6 -0.2 2.0 2.3

58.8 57.4 -1.4 1.1 1.3

38.8 38.8 0.0 0.6 0.8

19.2 19.8 0.6 0.6 0.7

S

0.4 -0.9 -1.3 0.4 0.6

20.0 18.2 -1.8 0.5 0.6

39.6 38.3 -1.3 0.3 0.3

59.6 57.5 -2.1 0.2 0.4

79.4 78.5 -0.9 0.2 0.2

89.2 89.2 0.0 0.1 0.1

91.2 91.3 0.1 0.1 0.2

93.2 93.4 0.2 0.1 0.1

95.2 95.5 0.3 0.3 0.3

97.2 97.5 0.3 0.2 0.2

99.0 99.6 0.6 0.1 0.1


311


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 99.0 0.4 0.3 0.3

96.8 96.5 -0.3 0.6 0.8

94.8 94.5 -0.3 0.4 0.4

92.8 92.7 -0.1 0.3 0.3

90.8 90.8 0.0 0.8 1.1

88.8 88.7 -0.1 0.8 1.0

78.8 79.5 0.7 0.7 0.8

58.8 57.8 -1.0 2.0 2.0

38.8 39.1 0.3 1.2 1.4

19.2 19.8 0.6 0.7 1.0

S

0.4 -1.1 -1.5 0.6 0.7

20.0 18.2 -1.8 0.6 0.7

39.6 38.3 -1.3 0.4 0.4

59.6 57.5 -2.1 0.4 0.5

79.4 78.4 -1.0 0.2 0.3

89.2 89.2 0.0 0.2 0.2

91.2 91.2 0.0 0.2 0.2

93.2 93.4 0.2 0.2 0.2

95.2 95.5 0.3 0.4 0.5

97.2 97.5 0.3 0.2 0.2

99.0 99.6 0.6 0.2 0.3



major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 98.9 0.3 0.4 0.4

96.8 96.6 -0.2 1.0 1.1

94.8 94.5 -0.3 1.2 1.4

92.8 92.9 0.1 1.0 1.2

90.8 90.8 0.0 1.1 1.4

88.8 88.5 -0.3 1.0 1.0

78.8 79.6 0.8 0.7 1.0

58.8 58.4 -0.4 2.2 2.6

38.8 39.4 0.6 2.0 2.4

19.2 20.1 0.9 1.8 2.3

S

0.4 -1.6 -2.0 1.3 1.5

20.0 17.7 -2.3 1.4 1.5

39.6 38.3 -1.3 0.7 0.9

59.6 57.4 -2.2 0.8 1.0

79.4 78.3 -1.1 0.3 0.4

89.2 89.1 -0.1 0.7 1.0

91.2 91.0 -0.2 0.4 0.5

93.2 93.3 0.1 0.3 0.4

95.2 95.4 0.2 0.9 1.1

97.2 97.3 0.1 0.3 0.4

99.0 99.4 0.4 0.3 0.3


312


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 99.2 0.6 0.9 1.0

96.8 96.6 -0.2 0.5 0.6

94.8 94.5 -0.3 0.4 0.5

92.8 92.7 -0.1 0.2 0.2

90.8 90.8 0.0 0.6 0.8

88.8 88.5 -0.3 1.1 1.6

78.8 79.5 0.7 1.0 1.3

58.8 58.5 -0.3 0.8 1.0

38.8 39.7 0.9 1.3 1.7

19.2 20.7 1.5 1.1 1.3

S

0.4 -1.4 -1.8 0.4 0.5

20.0 18.0 -2.0 0.7 0.9

39.6 38.3 -1.3 0.4 0.6

59.6 57.7 -1.9 0.4 0.4

79.4 78.6 -0.8 0.2 0.3

89.2 89.2 0.0 0.4 0.5

91.2 91.4 0.2 0.1 0.1

93.2 93.4 0.2 0.2 0.2

95.2 95.5 0.3 0.3 0.4

97.2 97.3 0.1 0.2 0.2

99.0 99.5 0.5 0.2 0.2



major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 96.3 -0.5 0.9 1.1

94.8 94.6 -0.2 1.1 1.1

92.8 92.9 0.1 1.0 1.1

90.8 90.2 -0.6 0.2 0.3

88.8 89.0 0.2 1.7 1.6

78.8 79.2 0.4 2.5 2.6

58.8 56.6 -2.2 1.0 1.3

38.8 38.0 -0.8 0.8 1.0

19.2 18.9 -0.3 0.3 0.3

S

0.4 0.0 -0.4 0.5 0.7

20.0 19.2 -0.8 0.5 0.6

39.6 39.0 -0.6 0.5 0.6

59.6 58.2 -1.4 0.2 0.2

79.4 79.1 -0.3 0.6 0.7

89.2 89.5 0.3 0.4 0.4

91.2 91.6 0.4 0.6 0.7

93.2 93.8 0.6 0.3 0.4

95.2 95.7 0.5 0.3 0.3

97.2 97.5 0.3 0.4 0.5

99.0 99.6 0.6 0.2 0.2

aAverage of five injections. bobs – calc. cSecond peak not detected.

313


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 95.9 -0.9 0.9 1.1

94.8 93.9 -0.9 0.6 0.7

92.8 92.3 -0.5 0.4 0.6

90.8 89.9 -0.9 1.3 1.5

88.8 88.0 -0.8 1.1 1.4

78.8 78.0 -0.8 1.0 1.1

58.8 56.7 -2.1 0.5 0.6

38.8 38.2 -0.6 0.6 0.8

19.2 18.9 -0.3 0.7 0.9

S

0.4 0.0 -0.4 0.3 0.4

20.0 19.3 -0.7 0.4 0.5

39.6 39.1 -0.5 0.3 0.4

59.6 58.3 -1.3 0.2 0.3

79.4 79.0 -0.4 0.3 0.3

89.2 89.5 0.3 0.2 0.2

91.2 91.6 0.4 0.2 0.2

93.2 93.6 0.4 0.3 0.3

95.2 95.6 0.4 0.2 0.3

97.2 97.4 0.2 0.2 0.3

99.0 99.5 0.5 0.5 0.6

aAverage of five injections. bobs – calc. cSecond peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 95.9 -0.9 0.8 1.0

94.8 93.4 -1.4 0.9 1.0

92.8 91.7 -1.1 1.1 1.1

90.8 89.9 -0.9 1.1 1.3

88.8 87.6 -1.2 0.9 1.1

78.8 77.9 -0.9 1.1 1.0

58.8 56.5 -2.3 0.4 0.5

38.8 37.9 -0.9 0.2 0.2

19.2 18.8 -0.4 0.6 0.8

S

0.4 -0.1 -0.5 0.4 0.6

20.0 19.3 -0.7 0.2 0.3

39.6 39.0 -0.6 0.3 0.3

59.6 58.1 -1.5 0.2 0.2

79.4 78.9 -0.5 0.2 0.2

89.2 89.4 0.2 0.2 0.2

91.2 91.5 0.3 0.1 0.2

93.2 93.6 0.4 0.2 0.2

95.2 95.6 0.4 0.2 0.2

97.2 97.4 0.2 0.2 0.2

99.0 99.6 0.6 0.3 0.4

aAverage of five injections. Negative number indicates excess of the opposite enantiomer. bobs – calc. cSecond peak not detected.

314


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 95.8 -1.0 0.8 1.0

94.8 93.3 -1.5 0.9 1.0

92.8 91.6 -1.2 1.1 1.2

90.8 89.8 -1.0 1.2 1.4

88.8 87.4 -1.4 0.9 1.2

78.8 77.6 -1.2 1.1 1.1

58.8 56.2 -2.6 0.4 0.5

38.8 37.6 -1.2 0.2 0.2

19.2 18.5 -0.7 0.7 0.8

S

0.4 -0.1 -0.5 0.3 0.4

20.0 19.4 -0.6 0.7 0.9

39.6 38.8 -0.8 0.3 0.4

59.6 57.9 -1.7 0.2 0.2

79.4 78.7 -0.7 0.2 0.3

89.2 89.3 0.1 0.2 0.2

91.2 91.4 0.2 0.2 0.2

93.2 93.5 0.3 0.2 0.2

95.2 95.5 0.3 0.2 0.2

97.2 97.4 0.2 0.2 0.3

99.0 99.7 0.7 0.3 0.4



major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 96.1 -0.7 0.5 0.6

94.8 93.7 -1.1 1.5 1.7

92.8 91.8 -1.0 1.3 1.6

90.8 89.9 -0.9 0.6 0.8

88.8 87.5 -1.3 1.2 1.3

78.8 77.6 -1.2 1.2 1.3

58.8 56.4 -2.4 1.0 1.3

38.8 37.6 -1.2 0.8 0.9

19.2 18.4 -0.8 0.7 0.9

S

0.4 -0.2 -0.6 0.3 0.4

20.0 19.2 -0.8 0.5 0.6

39.6 38.8 -0.8 0.4 0.5

59.6 58.0 -1.6 0.2 0.3

79.4 78.8 -0.6 0.3 0.4

89.2 89.3 0.1 0.3 0.4

91.2 91.5 0.3 0.3 0.4

93.2 93.5 0.3 0.2 0.2

95.2 95.5 0.3 0.2 0.3

97.2 97.4 0.2 0.3 0.4

99.0 99.5 0.5 0.5 0.7


315


Major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 96.2 -0.6 0.4 0.5

94.8 94.7 -0.1 1.0 1.1

92.8 92.6 -0.2 1.0 1.4

90.8 90.7 -0.1 1.0 1.3

88.8 88.7 -0.1 1.3 1.7

78.8 79.0 0.2 1.7 2.1

58.8 55.8 -3.0 0.6 0.7

38.8 37.2 -1.4 1.3 1.7

19.2 18.3 -0.9 0.8 0.9

S

0.4 -0.5 -0.9 0.3 0.4

20.0 19.4 -0.6 0.7 0.9

39.6 39.0 -0.6 0.6 0.7

59.6 58.2 -1.4 0.5 0.7

79.4 78.9 -0.5 0.6 0.8

89.2 89.3 0.1 0.6 0.6

91.2 91.5 0.3 0.7 0.8

93.2 93.7 0.5 0.4 0.5

95.2 95.6 0.4 0.3 0.4

97.2 97.4 0.2 0.6 0.7

99.0 99.3 0.3 0.9 1.0



major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0

96.8 96.2 -0.6 0.8 0.9

94.8 94.1 -0.7 0.3 0.3

92.8 92.2 -0.6 1.7 2.3

90.8 89.9 -0.9 0.9 1.1

88.8 88.6 -0.2 2.1 2.4

78.8 77.7 -1.1 0.9 1.1

58.8 57.1 -1.7 0.8 0.9

38.8 38.2 -0.6 0.6 0.7

19.2 19.1 -0.1 0.3 0.3

S

0.4 -0.1 -0.5 0.2 0.2

20.0 19.3 -0.7 0.3 0.5

39.6 39.2 -0.4 0.4 0.5

59.6 58.3 -1.3 0.3 0.3

79.4 79.2 -0.2 0.3 0.4

89.2 89.5 0.3 0.3 0.3

91.2 91.7 0.5 0.3 0.4

93.2 93.7 0.5 0.3 0.4

95.2 95.7 0.5 0.1 0.2

97.2 97.5 0.3 0.3 0.3

99.0 99.6 0.6 0.1 0.2


316


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 87.3 -1.5 0.8 1.0 78.8 76.1 -2.7 2.3 2.8

S

79.4 82.2 2.8 0.3 0.4 89.2 91.4 2.2 0.5 0.8 95.2 96.9 1.7 0.3 0.4 99.0 100d 1.0 0 0

aAverage of five injections. bobs – calc. cSecond peak not detected. dFirst

peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 85.8 -3.0 0.8 0.9 78.8 74.9 -3.9 1.0 1.3

S

79.4 81.8 2.4 0.3 0.3 89.2 91.1 1.8 0.1 0.1 95.2 96.6 1.4 0.1 0.2 99.0 100d 1.0 0 0


peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 85.8 -3.0 0.8 0.9 78.8 74.8 -4.1 1.0 1.3

S

79.4 81.7 2.3 0.2 0.3 89.2 91.0 1.8 0.1 0.1 95.2 96.6 1.4 0.1 0.2 99.0 100d 1.0 0 0


peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 85.8 -3.0 1.0 1.0 78.8 74.9 -3.9 0.7 1.0

S

79.4 81.7 2.3 0.3 0.3 89.2 91.0 1.8 0.1 0.1 95.2 96.6 1.4 0.1 0.2 99.0 100d 1.0 0 0


peak not detected.

317


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 86.0 -2.8 1.6 2.0 78.8 75.1 -3.7 0.7 0.9

S

79.4 81.8 2.4 0.3 0.4 89.2 91.1 1.8 0.1 0.2 95.2 96.6 1.4 0.2 0.2 99.0 100d 1.0 0 0


peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 86.5 -2.3 0.7 0.9 78.8 75.2 -3.6 0.6 0.7

S

79.4 82.0 2.6 0.6 0.7 89.2 91.2 1.9 0.2 0.3 95.2 96.7 1.5 0.3 0.4 99.0 100d 1.0 0 0


peak not detected.


major enantiomer

ee (%) error (%)b

2σ (%)

range (%) calc obsa

R

98.6 100c 1.4 0 0 94.8 100c 5.2 0 0 88.8 86.1 -2.7 0.6 0.8 78.8 75.2 -3.7 1.5 1.5

S

79.4 82.1 2.7 0.4 0.5 89.2 91.2 2.0 0.3 0.3 95.2 96.7 1.5 0.3 0.3 99.0 100d 1.0 0 0


peak not detected.

318

Table S23. Comparison of different slope sensitivity values on the determinations from a single

injection at 254 nm under 1% overlap conditions.

aValues of 100 indicate that the minor enantiomer was not detected despite being visible by eye. bValue

used for all chromatograms at 254 nm. cDefault value for our instrument. dA negative value indicates the

opposite enantiomer (R) is in excess.

major enantiomer

obs ee (%)a

Overlap (%) calc ee

(%) s = 0.1b s = 0.01 s = 0.05 s = 1 s = 5c

1

R

98.6 99.0 99.0 99.0 100.0 100.0 96.8 96.6 97.0 97.0 100.0 100.0 94.8 95.0 95.0 95.0 96.8 100.0 92.8 92.4 92.2 92.2 92.6 100.0 90.8 89.8 90.6 90.6 90.4 100.0 88.8 89.2 89.2 89.2 89.2 100.0 78.8 79.4 79.2 79.2 80.2 82.0 58.8 58.6 58.2 58.2 59.2 61.6 38.8 39.4 39.4 39.4 40.4 42.4 19.2 20.8 21.0 21.0 21.4 22.6

S

0.4 -1.4d -1.6d -1.4d -2.2d -2.6d 20.0 17.2 16.8 16.8 16.8 17.0 39.6 38.0 38.0 38.0 37.8 38.0 59.6 57.2 57.2 57.2 57.4 57.4 79.4 78.4 78.4 78.4 78.6 78.6 89.2 89.0 89.8 89.8 89.6 89.6 91.2 91.2 91.2 91.2 91.4 100.0 93.2 93.2 93.4 93.4 93.2 100.0 95.2 95.4 95.4 95.4 95.4 100.0 97.2 97.4 97.6 97.6 97.8 100.0 99.0 99.8 99.8 99.8 100.0 100.0

4

R

98.6 99.5 99.5 99.5 100.0 100.0

96.8 96.1 96.1 96.1 97.1 100.0

94.8 95.3 95.3 95.3 95.3 100.0

92.8 93.3 92.3 93.3 93.3 100.0

90.8 90.2 90.2 90.2 91.5 100.0

88.8 89.9 88.4 88.4 89.9 89.9

78.8 80.5 80.5 80.5 76.8 76.8

58.8 56.0 56.5 56.5 56.7 56.7

38.8 38.3 38.5 38.5 38.5 38.5

19.2 18.9 19.1 18.6 19.1 19.1

S

0.4 0.0 0.0 0.0 0.0 0.0 20.0 18.9 18.9 18.9 19.1 19.1 39.6 39.1 39.1 39.1 39.4 39.4 59.6 57.6 58.2 57.6 58.2 58.2 79.4 78.6 78.6 78.6 78.6 78.6 89.2 89.3 89.3 89.3 89.3 89.3 91.2 92.0 92.0 92.0 92.0 92.0 93.2 93.7 93.7 93.7 93.7 93.7 95.2 95.8 95.8 95.8 95.8 100.0 97.2 97.7 97.7 97.7 97.7 100.0 99.0 99.7 99.7 99.7 100.0 100.0

17

R

98.6 100.0 100.0 100.0 100.0 100.0

94.8 100.0 100.0 100.0 100.0 100.0

88.8 87.0 86.9 86.9 87.0 100.0

78.8 75.5 75.5 75.5 75.5 75.5

S

79.4 82.3 82.3 82.3 82.3 82.3 89.2 91.4 91.4 91.4 91.4 91.4 95.2 96.5 96.5 96.5 96.5 100.0 99.0 100.0 100.0 100.0 100.0 100.0

319

Reproducibility plots at single wavelengths. The figures below show the reproducibility of the measurements for samples with ≥

88% ee and resolutions corresponding to 1% and 4% overlap in racemic samples. Error bars are given by the uncertainties (2σ) derived

from all five determinations for each sample. Open circles are used for when the major enantiomer elutes off the column after the minor

enantiomer whereas filled circles are used for the opposite order. Black diamonds are used in the latter case when the minor component

was not detected with the integrator.

Figure S3. Reproducibility plots at 254 nm with peak resolutions corresponding to 1% (left) and 4% (right) overlap.

86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)

Average Observed ee (%)

86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100C

alcu

late

d e

e (%

)


320


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


321


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


322


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


323


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


324


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


325


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


86

88

90

92

94

96

98

100

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100

Cal

cula

ted

ee

(%)


326

Table S24. Comparison of data in Table 1 using 5 injections versus 3 injections.

calc ee (%) trial obs ee (%) trials avg obs ee (%) 2σ

98.6

1 98.9 1,2,3 98.9 0.2

2 98.8 1,2,4 98.9 0.2

3 99.0 1,2,5 98.9 0.3

4 99.0 1,3,4 99.0 0.1

5 99.1 1,3,5 99.0 0.1

avg. 99.0 1,4,5 99.0 0.2

2σ 0.2 2,3,4 98.9 0.2 2,3,5 99.0 0.3 2,4,5 99.0 0.3

3,4,5 99.0 0.1

96.8

1 96.7 1,2,3 96.4 0.4

2 96.3 1,2,4 96.6 0.5

3 96.4 1,2,5 96.6 0.7

4 96.7 1,3,4 96.6 0.4

5 96.9 1,3,5 96.7 0.4

avg. 96.6 1,4,5 96.8 0.3

2σ 0.6 2,3,4 96.5 0.5 2,3,5 96.5 0.7 2,4,5 96.6 0.7

3,4,5 96.7 0.6

94.8

1 94.3 1,2,3 94.6 0.4

2 94.7 1,2,4 94.5 0.4

3 94.6 1,2,5 94.6 0.5

4 94.4 1,3,4 94.5 0.2

5 94.7 1,3,5 94.6 0.2

avg. 94.6 1,4,5 94.5 0.4

2σ 0.4 2,3,4 94.6 0.3 2,3,5 94.7 0.2 2,4,5 94.6 0.3

3,4,5 94.6 0.3

92.8

1 92.6 1,2,3 92.7 0.3

2 92.7 1,2,4 92.7 0.3

3 92.9 1,2,5 92.7 0.1

4 92.9 1,3,4 92.8 0.3

5 92.7 1,3,5 92.8 0.3

avg. 92.8 1,4,5 92.8 0.3

2σ 0.3 2,3,4 92.8 0.3 2,3,5 92.8 0.3 2,4,5 92.8 0.3

3,4,5 92.9 0.2

90.8

1 90.8 1,2,3 90.8 0.4

2 90.6 1,2,4 90.7 0.3

3 91.0 1,2,5 90.8 0.4

4 90.9 1,3,4 90.9 0.2

5 91.0 1,3,5 90.9 0.2

avg. 90.8 1,4,5 90.9 0.2

2σ 0.3 2,3,4 90.8 0.4 2,3,5 90.8 0.5 2,4,5 90.8 0.4

3,4,5 90.9 0.1

327

88.8

1 89.0 1,2,3 88.7 0.6

2 88.6 1,2,4 88.8 0.5

3 88.5 1,2,5 89.0 0.9

4 88.7 1,3,4 88.7 0.5

5 89.4 1,3,5 89.0 0.5

avg. 88.8 1,4,5 89.0 0.7

2σ 0.8 2,3,4 88.6 0.2 2,3,5 88.8 1.1 2,4,5 88.9 0.9

3,4,5 88.9 1.0

78.8

1 78.4 1,2,3 78.4 2.3

2 79.6 1,2,4 79.2 1.3

3 77.3 1,2,5 79.2 1.3

4 79.4 1,3,4 78.4 2.2

5 79.4 1,3,5 78.4 2.2

avg. 78.8 1,4,5 79.1 1.2

2σ 2.0 2,3,4 78.8 2.6 2,3,5 78.8 2.6 2,4,5 79.5 0.2

3,4,5 78.7 2.5

58.8

1 58.8 1,2,3 58.2 1.7

2 58.6 1,2,4 58.4 1.1

3 57.2 1,2,5 58.3 1.5

4 57.8 1,3,4 57.9 1.6

5 57.4 1,3,5 57.8 1.6

avg. 57.9 1,4,5 58.0 1.5

2σ 1.4 2,3,4 57.8 1.4 2,3,5 57.7 1.5 2,4,5 57.9 1.2

3,4,5 57.5 0.6

38.8

1 39.2 1,2,3 39.4 0.5

2 39.6 1,2,4 39.6 0.9

3 39.5 1,2,5 39.2 0.8

4 40.1 1,3,4 39.6 0.9

5 38.8 1,3,5 39.2 0.9

avg. 39.5 1,4,5 39.4 1.3

2σ 0.9 2,3,4 39.8 0.6 2,3,5 39.3 0.9 2,4,5 39.5 1.3

3,4,5 39.5 1.2

19.2

1 20.4 1,2,3 20.1 0.8

2 19.6 1,2,4 20.0 0.8

3 20.2 1,2,5 20.1 0.8

4 20.1 1,3,4 20.2 0.3

5 20.2 1,3,5 20.3 0.3

avg. 20.1 1,4,5 20.2 0.3

2σ 0.6 2,3,4 20.0 0.6 2,3,5 20.0 0.7 2,4,5 19.9 0.6

3,4,5 20.2 0.2

328


calc ee (%) trial obs ee (%) trials avg obs ee (%) 2σ

98.6

1 100.0 1,2,3 100.0 0.0

2 100.0 1,2,4 100.0 0.0

3 100.0 1,2,5 100.0 0.0

4 100.0 1,3,4 100.0 0.0

5 100.0 1,3,5 100.0 0.0

avg. 100.0 1,4,5 100.0 0.0

2σ 0.0 2,3,4 100.0 0.0 2,3,5 100.0 0.0 2,4,5 100.0 0.0

3,4,5 100.0 0.0

96.8

1 95.6 1,2,3 96.0 0.7

2 96.3 1,2,4 96.0 0.7

3 96.1 1,2,5 95.7 1.1

4 96.0 1,3,4 95.9 0.5

5 95.2 1,3,5 95.6 0.5

avg. 95.9 1,4,5 95.6 0.9

2σ 0.9 2,3,4 96.2 0.3 2,3,5 95.9 1.2 2,4,5 95.8 1.2

3,4,5 95.8 1.1

94.8

1 94.2 1,2,3 93.6 1.0

2 93.5 1,2,4 93.9 0.8

3 93.3 1,2,5 93.9 0.7

4 94.2 1,3,4 93.9 1.1

5 94.0 1,3,5 93.8 1.1

avg. 93.8 1,4,5 94.1 0.2

2σ 0.8 2,3,4 93.6 0.9 2,3,5 93.6 0.7 2,4,5 93.9 0.7

3,4,5 93.8 1.0

92.8

1 92.1 1,2,3 92.2 0.6

2 92.0 1,2,4 92.0 0.2

3 92.5 1,2,5 92.1 0.4

4 91.9 1,3,4 92.2 0.7

5 92.3 1,3,5 92.3 0.7

avg. 92.2 1,4,5 92.1 0.5

2σ 0.5 2,3,4 92.1 0.7 2,3,5 92.3 0.6 2,4,5 92.1 0.5

3,4,5 92.3 0.7

90.8

1 89.7 1,2,3 90.1 0.7

2 90.4 1,2,4 90.1 0.7

3 90.3 1,2,5 89.6 1.5

4 90.3 1,3,4 90.1 0.6

5 88.9 1,3,5 89.6 0.6

avg. 89.9 1,4,5 89.6 1.4

2σ 1.3 2,3,4 90.3 0.1 2,3,5 89.8 1.7 2,4,5 89.8 1.7

3,4,5 89.8 1.6

329

88.8

1 88.5 1,2,3 87.8 1.4

2 87.1 1,2,4 88.0 1.5

3 88.0 1,2,5 88.0 1.5

4 88.3 1,3,4 88.3 0.4

5 88.3 1,3,5 88.3 0.4

avg. 88.0 1,4,5 88.4 0.1

2σ 1.1 2,3,4 87.8 1.3 2,3,5 87.8 1.3 2,4,5 87.9 1.5

3,4,5 88.2 0.4

78.8

1 77.6 1,2,3 78.2 1.1

2 78.7 1,2,4 78.0 1.3

3 78.2 1,2,5 78.0 1.3

4 77.6 1,3,4 77.8 0.7

5 77.6 1,3,5 77.8 0.7

avg. 78.0 1,4,5 77.6 0.1

2σ 1.0 2,3,4 78.2 1.1 2,3,5 78.2 1.1 2,4,5 78.0 1.2

3,4,5 77.8 0.7

58.8

1 56.3 1,2,3 56.6 0.4

2 56.7 1,2,4 56.6 0.5

3 56.6 1,2,5 56.7 0.6

4 56.8 1,3,4 56.6 0.4

5 56.9 1,3,5 56.6 0.4

avg. 56.7 1,4,5 56.7 0.6

2σ 0.4 2,3,4 56.7 0.2 2,3,5 56.8 0.3 2,4,5 56.8 0.2

3,4,5 56.8 0.3

38.8

1 38.7 1,2,3 38.3 0.9

2 38.0 1,2,4 38.2 0.9

3 38.0 1,2,5 38.3 0.8

4 38.0 1,3,4 38.3 0.8

5 38.1 1,3,5 38.3 0.8

avg. 38.2 1,4,5 38.3 0.8

2σ 0.6 2,3,4 38.0 0.1 2,3,5 38.0 0.2 2,4,5 38.0 0.2

3,4,5 38.1 0.1

19.2

1 18.4 1,2,3 18.9 0.9

2 18.9 1,2,4 18.8 0.8

3 19.3 1,2,5 18.7 0.5

4 19.2 1,3,4 19.0 0.9

5 18.8 1,3,5 18.9 0.9

avg. 18.9 1,4,5 18.8 0.7

2σ 0.7 2,3,4 19.1 0.4 2,3,5 19.0 0.5 2,4,5 19.0 0.3

3,4,5 19.1 0.5

330


calc ee (%) trial obs ee (%)a trials avg obs ee (%) 2σ

99.0

1 99.7 1,2,3 99.6 0.1

2 99.6 1,2,4 99.6 0.1

3 99.6 1,2,5 99.6 0.1

4 99.6 1,3,4 99.6 0.1

5 99.6 1,3,5 99.6 0.1

avg. 99.6 1,4,5 99.6 0.1

2σ 0.1 2,3,4 99.6 0.1 2,3,5 99.6 0.1 2,4,5 99.6 0.1

3,4,5 99.6 0.1

97.2

1 97.5 1,2,3 97.5 0.1

2 97.4 1,2,4 97.5 0.2

3 97.4 1,2,5 97.5 0.1

4 97.6 1,3,4 97.5 0.2

5 97.5 1,3,5 97.5 0.2

avg. 97.5 1,4,5 97.5 0.1

2σ 0.2 2,3,4 97.5 0.2 2,3,5 97.4 0.1 2,4,5 97.5 0.2

3,4,5 97.5 0.2

95.2

1 95.4 1,2,3 95.6 0.2

2 95.6 1,2,4 95.6 0.2

3 95.7 1,2,5 95.5 0.2

4 95.6 1,3,4 95.6 0.2

5 95.4 1,3,5 95.5 0.2

avg. 95.6 1,4,5 95.5 0.2

2σ 0.2 2,3,4 95.6 0.0 2,3,5 95.6 0.2 2,4,5 95.6 0.2

3,4,5 95.6 0.2

93.2

1 93.5 1,2,3 93.5 0.1

2 93.4 1,2,4 93.5 0.1

3 93.5 1,2,5 93.4 0.0

4 93.5 1,3,4 93.5 0.1

5 93.4 1,3,5 93.5 0.1

avg. 93.5 1,4,5 93.5 0.1

2σ 0.1 2,3,4 93.5 0.2 2,3,5 93.5 0.1 2,4,5 93.5 0.1

3,4,5 93.5 0.1

91.2

1 91.4 1,2,3 91.4 0.1

2 91.5 1,2,4 91.4 0.2

3 91.4 1,2,5 91.4 0.2

4 91.3 1,3,4 91.3 0.1

5 91.3 1,3,5 91.4 0.1

avg. 91.4 1,4,5 91.3 0.1

2σ 0.1 2,3,4 91.4 0.2 2,3,5 91.4 0.2 2,4,5 91.3 0.2

3,4,5 91.3 0.1

331

89.2

1 89.3 1,2,3 89.4 0.3

2 89.5 1,2,4 89.4 0.2

3 89.3 1,2,5 89.4 0.3

4 89.4 1,3,4 89.4 0.1

5 89.3 1,3,5 89.3 0.1

avg. 89.4 1,4,5 89.3 0.2

2σ 0.2 2,3,4 89.4 0.2 2,3,5 89.4 0.3 2,4,5 89.4 0.3

3,4,5 89.3 0.1

79.4

1 78.7 1,2,3 78.6 0.2

2 78.6 1,2,4 78.7 0.1

3 78.5 1,2,5 78.7 0.1

4 78.7 1,3,4 78.6 0.2

5 78.7 1,3,5 78.7 0.2

avg. 78.7 1,4,5 78.7 0.1

2σ 0.2 2,3,4 78.6 0.1 2,3,5 78.6 0.2 2,4,5 78.7 0.1

3,4,5 78.6 0.2

59.6

1 57.7 1,2,3 57.7 0.4

2 57.6 1,2,4 57.7 0.2

3 57.9 1,2,5 57.7 0.2

4 57.7 1,3,4 57.8 0.2

5 57.8 1,3,5 57.8 0.2

avg. 57.7 1,4,5 57.7 0.0

2σ 0.3 2,3,4 57.7 0.4 2,3,5 57.8 0.4 2,4,5 57.7 0.2

3,4,5 57.8 0.2

39.6

1 38.6 1,2,3 38.5 0.3

2 38.3 1,2,4 38.4 0.3

3 38.6 1,2,5 38.5 0.4

4 38.3 1,3,4 38.5 0.3

5 38.6 1,3,5 38.6 0.3

avg. 38.5 1,4,5 38.5 0.3

2σ 0.3 2,3,4 38.4 0.3 2,3,5 38.5 0.4 2,4,5 38.4 0.4

3,4,5 38.5 0.3

20.0

1 17.9 1,2,3 18.2 0.6

2 18.3 1,2,4 18.1 0.4

3 18.4 1,2,5 18.2 0.6

4 18.1 1,3,4 18.2 0.5

5 18.4 1,3,5 18.3 0.5

avg. 18.2 1,4,5 18.2 0.5

2σ 0.5 2,3,4 18.3 0.3 2,3,5 18.4 0.2 2,4,5 18.3 0.3

3,4,5 18.3 0.4

332


calc ee (%) trial obs ee (%)a trials avg obs eea 2σ

99.0

1 99.7 1,2,3 99.5 0.6

2 99.7 1,2,4 99.6 0.1

3 99.1 1,2,5 99.6 0.2

4 99.6 1,3,4 99.5 0.6

5 99.5 1,3,5 99.4 0.6

avg. 99.5 1,4,5 99.6 0.2

2σ 0.5 2,3,4 99.5 0.6 2,3,5 99.4 0.6 2,4,5 99.6 0.2

3,4,5 99.4 0.5

97.2

1 97.6 1,2,3 97.5 0.2

2 97.5 1,2,4 97.4 0.3

3 97.4 1,2,5 97.5 0.1

4 97.3 1,3,4 97.4 0.3

5 97.5 1,3,5 97.5 0.3

avg. 97.4 1,4,5 97.5 0.3

2σ 0.2 2,3,4 97.4 0.2 2,3,5 97.5 0.1 2,4,5 97.4 0.3

3,4,5 97.4 0.2

95.2

1 95.8 1,2,3 95.6 0.2

2 95.6 1,2,4 95.6 0.3

3 95.5 1,2,5 95.7 0.2

4 95.5 1,3,4 95.6 0.3

5 95.6 1,3,5 95.6 0.3

avg. 95.6 1,4,5 95.6 0.3

2σ 0.2 2,3,4 95.6 0.2 2,3,5 95.6 0.1 2,4,5 95.6 0.2

3,4,5 95.5 0.1

93.2

1 93.7 1,2,3 93.5 0.3

2 93.5 1,2,4 93.6 0.2

3 93.4 1,2,5 93.6 0.2

4 93.6 1,3,4 93.6 0.3

5 93.6 1,3,5 93.6 0.3

avg. 93.6 1,4,5 93.6 0.1

2σ 0.2 2,3,4 93.5 0.1 2,3,5 93.5 0.2 2,4,5 93.6 0.1

3,4,5 93.5 0.2

91.2

1 91.7 1,2,3 91.6 0.2

2 91.5 1,2,4 91.6 0.2

3 91.5 1,2,5 91.6 0.2

4 91.6 1,3,4 91.6 0.1

5 91.6 1,3,5 91.6 0.1

avg. 91.6 1,4,5 91.6 0.1

2σ 0.2 2,3,4 91.6 0.2 2,3,5 91.5 0.1 2,4,5 91.6 0.2

3,4,5 91.6 0.1

333

89.2

1 89.3 1,2,3 89.4 0.2

2 89.5 1,2,4 89.5 0.3

3 89.3 1,2,5 89.5 0.2

4 89.6 1,3,4 89.4 0.3

5 89.5 1,3,5 89.4 0.3

avg. 89.5 1,4,5 89.5 0.3

2σ 0.2 2,3,4 89.5 0.2 2,3,5 89.5 0.2 2,4,5 89.5 0.1

3,4,5 89.5 0.2

79.4

1 78.8 1,2,3 79.0 0.3

2 79.1 1,2,4 79.0 0.3

3 79.0 1,2,5 79.0 0.3

4 79.1 1,3,4 79.0 0.3

5 79.1 1,3,5 79.0 0.3

avg. 79.0 1,4,5 79.0 0.3

2σ 0.3 2,3,4 79.1 0.1 2,3,5 79.1 0.1 2,4,5 79.1 0.1

3,4,5 79.1 0.1

59.6

1 58.2 1,2,3 58.2 0.1

2 58.2 1,2,4 58.2 0.1

3 58.2 1,2,5 58.3 0.3

4 58.3 1,3,4 58.2 0.1

5 58.4 1,3,5 58.3 0.1

avg. 58.3 1,4,5 58.3 0.3

2σ 0.2 2,3,4 58.3 0.1 2,3,5 58.3 0.2 2,4,5 58.3 0.2

3,4,5 58.3 0.2

39.6

1 39.3 1,2,3 39.1 0.4

2 39.0 1,2,4 39.1 0.4

3 38.9 1,2,5 39.1 0.4

4 39.1 1,3,4 39.1 0.4

5 38.9 1,3,5 39.1 0.4

avg. 39.1 1,4,5 39.1 0.4

2σ 0.3 2,3,4 39.0 0.2 2,3,5 38.9 0.0 2,4,5 39.0 0.2

3,4,5 39.0 0.2

20.0

1 19.3 1,2,3 19.3 0.1

2 19.3 1,2,4 19.2 0.4

3 19.4 1,2,5 19.3 0.2

4 18.9 1,3,4 19.2 0.5

5 19.4 1,3,5 19.4 0.5

avg. 19.3 1,4,5 19.2 0.5

2σ 0.4 2,3,4 19.2 0.5 2,3,5 19.4 0.2 2,4,5 19.2 0.5

3,4,5 19.2 0.6

334

Propagation of the uncertainty across multiple wavelengths. The use of multiple

wavelengths (220, 225, 230, and 235 nm) to improve the accuracy and reproducibility of

these measurements was explored (Table S23). Propagated uncertainties (2σprop) for the

multiple wavelength data were calculated using the following equation:

2𝜎𝑝𝑟𝑜𝑝 = √2𝜎220

2 + 2𝜎2252 + 2𝜎230

2 + 2𝜎2352

4

Little effect on the errors for the observed ees was found because peak resolution is

wavelength independent in the absence of impurities that absorb at only some of the

monitored wavelengths. The precision (2σ) was increased by averaging the results using

four wavelengths as expected.

Table S28. Comparison of data collected at 220 nm and using multiple

wavelengths for 1% resolution.

major

enantiomer calc ee (%) 220 nm multiple wavelengths

obs ee (%)a error (%)b obs ee (%)a error (%)b

R

98.6 99.0 ± 0.2 0.4 98.9 ± 0.2 0.3

96.8 96.6 ± 0.6 -0.2 96.5 ± 0.3 -0.3

94.8 94.6 ± 0.4 -0.2 94.5 ± 0.2 -0.3

92.8 92.8 ± 0.3 0.0 92.7 ± 0.1 -0.1

90.8 90.8 ± 0.3 0.0 90.8 ± 0.3 0.0

88.8 88.8 ± 0.8 0.0 88.7 ± 0.4 -0.1

78.8 78.8 ± 2.0 0.0 78.9 ± 0.9 0.1

58.8 57.9 ± 1.4 -0.9 57.7 ± 0.7 -1.1

38.8 39.5 ± 0.9 0.7 39.1 ± 0.4 0.3

19.2 20.1 ± 0.6 0.9 19.9 ± 0.3 0.7

S

0.4 -1.0 ± 0.4 -1.4 -1.0 ± 0.2 -1.4 20.0 18.2 ± 0.5 -1.8 18.2 ± 0.2 -1.8 39.6 38.5 ± 0.3 -1.1 38.4 ± 0.2 -1.2 59.6 57.7 ± 0.3 -1.9 57.6 ± 0.1 -2.0 79.4 78.7 ± 0.2 -0.7 78.5 ± 0.1 -0.9 89.2 89.4 ± 0.2 0.2 89.3 ± 0.1 0.1 91.2 91.4 ± 0.1 0.2 91.3 ± 0.1 0.1 93.2 93.5 ± 0.1 0.3 93.4 ± 0.1 0.2 95.2 95.6 ± 0.2 0.4 95.5 ± 0.1 0.3 97.2 97.5 ± 0.2 0.3 97.5 ± 0.1 0.3 99.0 99.6 ± 0.1 0.6 99.6 ± 0.1 0.6

aavg. of 5 injections. Uncertainty given as 2σ. bobs – calc.

335

Selectivity factor (α) and resolution (Rs). The selectivity factor (α) and resolution (Rs)

were calculated for all of the sample chromatograms provided below (Figures S13-S63)

using the following equations and given in Tables S29-S31:

𝛼 = 𝑡𝑟2

𝑡𝑟1

𝑅𝑠 = 1.18(𝑡𝑟2 − 𝑡𝑟1)

(𝑤1 + 𝑤2)

where tr2 and tr1 are the retention times (corrected for the unretained time) of the second

and first peaks, respectively, and w1 and w2 are the widths of the peaks at their half

heights. Note: if one wants to use the width at the base of peaks, one must multiply by 2

instead of 1.18.

Table S29. Calculated α and Rs values for the 1% overlap data.

Major Enantiomer

calc ee (%)

tr1 (min) tr2 (min) w1 (min) w2 (min) α Rs

R

98.6 2.068 3.545 0.2842 0.4117 1.71 2.50

96.8 2.072 3.578 0.2807 0.4329 1.73 2.49

94.8 2.096 3.638 0.2867 0.4407 1.74 2.50

92.8 2.098 3.639 0.2869 0.4312 1.73 2.53

90.8 2.102 3.641 0.2867 0.4173 1.73 2.58

88.8 2.111 3.660 0.2877 0.4138 1.73 2.61

78.8 2.111 3.638 0.2863 0.4021 1.72 2.62

58.8 2.116 3.607 0.2846 0.3944 1.70 2.59

38.8 2.120 3.582 0.2851 0.3931 1.69 2.54

19.2 2.130 3.573 0.2826 0.3945 1.68 2.51

S

0.4 2.032 3.365 0.2764 0.3865 1.66 2.37

20.0 2.149 3.556 0.2855 0.3977 1.65 2.43

39.6 2.157 3.539 0.2829 0.3979 1.64 2.40

59.6 2.166 3.530 0.2841 0.3992 1.63 2.36

79.4 2.184 3.530 0.2863 0.3989 1.62 2.32

89.2 2.191 3.526 0.2844 0.3985 1.61 2.31

91.2 2.187 3.507 0.2829 0.3971 1.60 2.29

93.2 2.190 3.505 0.2809 0.3967 1.60 2.29

95.2 2.192 3.490 0.2725 0.3948 1.59 2.30

97.2 2.203 3.512 0.2774 0.4022 1.59 2.27

99.0 2.190 3.489 0.2652 0.3953 1.59 2.32

336

Table S30. Calculated α and Rs values for the 4% overlap data.a

Major Enantiomer

calc ee (%)


R

98.6 1.522 - 0.2853 - - -

96.8 1.529 2.511 0.2789 0.4018 1.64 1.70

94.8 1.521 2.499 0.2771 0.3668 1.64 1.79

92.8 1.531 2.520 0.2830 0.3690 1.65 1.79

90.8 1.536 2.537 0.2794 0.3827 1.65 1.78

88.8 1.536 2.535 0.2791 0.3631 1.65 1.84

78.8 1.538 2.527 0.2777 0.3722 1.64 1.80

58.8 1.543 2.517 0.2766 0.3597 1.63 1.81

38.8 1.543 2.501 0.2753 0.3516 1.62 1.80

19.2 1.544 2.488 0.2700 0.3472 1.61 1.80

S

0.4 1.526 2.442 0.2715 0.3433 1.60 1.76

20.0 1.554 2.478 0.2726 0.3405 1.59 1.78

39.6 1.558 2.469 0.2680 0.3453 1.58 1.75

59.6 1.561 2.458 0.2671 0.3392 1.57 1.75

79.4 1.571 2.457 0.2681 0.3406 1.56 1.72

89.2 1.571 2.450 0.2678 0.3429 1.56 1.70

91.2 1.576 2.456 0.2672 0.3433 1.56 1.70

93.2 1.573 2.448 0.2615 0.3413 1.56 1.71

95.2 1.578 2.455 0.2621 0.3426 1.56 1.71

97.2 1.562 2.418 0.2644 0.3348 1.55 1.69

99.0 1.574 2.436 0.2488 0.3371 1.55 1.74 aHyphens indicate the peak was not detected.

Table S31. Calculated α and Rs values for the 17% overlap data.a

Major Enantiomer

calc ee (%)


R

98.6 1.262 - 0.2203 - - -

94.8 1.266 - 0.2250 - - -

88.8 1.265 1.712 0.2175 0.2245 1.35 1.19

78.8 1.257 1.722 0.2149 0.2354 1.37 1.22

S

79.4 1.274 1.721 0.1929 0.2493 1.35 1.19

89.2 1.276 1.719 0.1780 0.2501 1.35 1.22

95.2 1.280 1.716 0.1564 0.2500 1.34 1.27

99.0 - 1.718 - 0.2535 - -

racemic sample

- 1.266 1.725 0.1867 0.2191 1.36 1.33

aHyphens indicate the peak was not detected.

337

Figure S10. A comparison of the error in the ee (%) versus the chromatogram resolution

(Rs), where positive and negative numbers indicate the observed value is too large or

too small compared to the true value, respectively. Triangles, squares, and circles

represent 17, 4, and 1% data, respectively. Filled and unfilled symbols are for when the

major enantiomer elutes off the column first and second respectively.

Figure S11. A comparison of the uncertainty in the ee (2σ) versus the α value of the

separation. Triangles, squares, and circles represent 17, 4, and 1% data, respectively.

Filled and unfilled symbols are for when the major enantiomer elutes off the column first

and second respectively.

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80

erro

r (%

)

Rs

0.0

0.5

1.0

1.5

2.0

2.5

1.20 1.30 1.40 1.50 1.60 1.70 1.80

2σ

(±%

)

α

338

Figure S12. A comparison of the error in the ee (%) versus the α value of the

separation, where positive and negative numbers indicate the observed value is too

large or too small compared to the true value, respectively. Triangles, squares, and

circles represent 17, 4, and 1% data, respectively. Filled and unfilled symbols are for

when the major enantiomer elutes off the column first and second respectively.

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

1.20 1.30 1.40 1.50 1.60 1.70 1.80

erro

r (%

)

α

339

Representative Chromatographs Obtained at 220 nm. The (R)-enantiomer elutes first

in all cases.

Figure S13. Chromatogram of a racemic mixture separated with 1% overlap.

Figure S14. Chromatogram of (R)-3.1 (98.6% ee) separated with 1% overlap.


340




341




342



Figure S24. Chromatogram of (S)-3.1 (20.0% ee) separated with 1% overlap.

343




344




345




346

Figure S34. Chromatogram of a racemic mixture separated with 4% overlap.



347




348




349




350




351




352




353

Figure S55. Chromatogram of racemic mixture separated with 17% overlap.


354

Figure S57. Chromatogram of (R)-3.1 (94.8% ee) separated with 17% overlap (top – full

spectrum, bottom – enlarged to show shoulder).


355




356



357

Appendix for Chapter 4 HPLC Chromatograms and Data1

Friedel-Crafts Alkylations in CDCl32

Purified Solvent. Reaction temperature = rt. Five injections collected at 280 nm.a

Trial Area (Peak 1) Area (Peak 2) Total Area % Area (Peak 1) % Area (Peak 2)

1 9916.9 5839 15755.9 62.9 37.1

2 9898.2 5827.7 15725.9 62.9 37.1

3 9881.5 5815.2 15696.7 63.0 37.0

4 9924.4 5840.6 15765 63.0 37.0

5 9947.7 5856.9 15804.6 62.9 37.1

Average 62.9 37.1

Standard Dev. 0.01 0.01 aAverage values from 220 and 230 nm: 62.8:37.2 and 62.7:37.3, respectively.

Catalyst (10 mol%):

358

Purified Solvent. Reaction temperature = -35 °C. Five injections collected at 280 nm.a


1 7526.6 2053.5 9580.1 78.6 21.4

2 7495.4 2036.1 9531.5 78.6 21.4

3 7581.4 2135.1 9716.5 78.0 22.0

4 7543.2 2050.8 9594 78.6 21.4

5 7524.6 2051.9 9576.5 78.6 21.4 Average 78.5 21.5 Standard Dev. 0.26 0.26

aAverage values from 220 and 230 nm: 78.5: 21.5 and 78.3:21.7, respectively.

Catalyst (10 mol%):

359

Unpurified Solvent. Reaction temperature = -35 °C. Five injections collected at 280 nm.a


1 5440.9 1087.2 6528.1 83.3 16.7

2 5451.3 1090.1 6541.4 83.3 16.7

3 5462.9 1090.7 6553.6 83.4 16.6

4 5469 1091.9 6560.9 83.4 16.6

5 5519.3 1103.9 6623.2 83.3 16.7

Average 83.3 16.7


Catalyst (10 mol%):

360



1 7920.1 1786.9 9707 81.6 18.4

2 7044 1576.3 8620.3 81.7 18.3

3 7060 1580.1 8640.1 81.7 18.3

4 7066.2 1580.1 8646.3 81.7 18.3

5 7087.5 1585.2 8672.7 81.7 18.3 Average 81.7 18.3


Catalyst (10 mol%) and cocatalyst (10 mol%):

361



1 7908.6 1536.8 9445.4 83.7 16.3

2 7942.1 1558 9500.1 83.6 16.4

3 7958.8 1555.6 9514.4 83.7 16.3

4 7940 1545.1 9485.1 83.7 16.3

5 7973.7 1559.1 9532.8 83.6 16.4 Average 83.7 16.3



362



1 8094.6 3143.4 11238 72.0 28.0

2 8049.6 3121.4 11171 72.1 27.9

3 8088.8 3137.2 11226 72.1 27.9

4 8092 3140.2 11232.2 72.0 28.0

5 8115.1 3149.7 11264.8 72.0 28.0 Average 72.0 28.0



363



1 6552.2 2441.1 8993.3 72.9 27.1

2 6539.8 2435.8 8975.6 72.9 27.1

3 6561.2 2443.7 9004.9 72.9 27.1

4 6578 2449.7 9027.7 72.9 27.1

5 6590 2453.1 9043.1 72.9 27.1 Average 72.9 27.1


HCl washed Catalyst (10 mol%):

364



1 7447.3 2537.3 9984.6 74.6 25.4

2 7451.6 2539.9 9991.5 74.6 25.4

3 7459.3 2544.3 10003.6 74.6 25.4

4 7501.4 2553.7 10055.1 74.6 25.4

5 7526.7 2566.1 10092.8 74.6 25.4 Average 74.6 25.4



365



1 13304.6 2754.6 16059.2 82.8 17.2

2 13375 2766.3 16141.3 82.9 17.1

3 13400.8 2774.2 16175 82.8 17.2

4 13454.1 2787.1 16241.2 82.8 17.2

5 13486.8 2791.8 16278.6 82.8 17.2 Average 82.8 17.2



366

Friedel-Crafts Alkylations in CD2Cl22



1 5101.4 3098.1 8199.5 62.2 37.8

2 5086.9 3093.8 8180.7 62.2 37.8

3 5108.9 3102.9 8211.8 62.2 37.8

4 5129.4 3115.2 8244.6 62.2 37.8

5 5126.6 3115.5 8242.1 62.2 37.8 Average 62.2 37.8


Catalyst (10 mol%):

367



1 14897.5 4705.4 19602.9 76.0 24.0

2 14899.1 4705.6 19604.7 76.0 24.0

3 14922.9 4711.3 19634.2 76.0 24.0

4 14934.9 4716.4 19651.3 76.0 24.0

5 14983.9 4732 19715.9 76.0 24.0 Average 76.0 24.0



368



1 11099.4 2848.5 13947.9 79.6 20.4

2 11076 2842.7 13918.7 79.6 20.4

3 11118.9 2853.3 13972.2 79.6 20.4

4 11144.5 2860.5 14005 79.6 20.4

5 11179.9 2868.2 14048.1 79.6 20.4 Average 79.6 20.4



369



1 3524.9 963.2 4488.1 78.5 21.5

2 3545.6 968.9 4514.5 78.5 21.5

3 3542.9 966.8 4509.7 78.6 21.4

4 3548.9 968.5 4517.4 78.6 21.4

5 3558.1 971 4529.1 78.6 21.4 Average 78.6 21.4



370



1 17200.1 4283 21483.1 80.1 19.9

2 17154.2 4273.9 21428.1 80.1 19.9

3 17141.4 4270 21411.4 80.1 19.9

4 17140.4 4267.8 21408.2 80.1 19.9

5 17190.6 4280.4 21471 80.1 19.9 Average 80.1 19.9



371



1 2532.1 635.4 3167.5 79.9 20.1

2 0b 0b 0b - -

3 2697.1 677.2 3374.3 79.9 20.1

4 2687.8 675.5 3363.3 79.9 20.1

5 2705.4 678.3 3383.7 80.0 20.0 Average 79.9 20.1


bComputer crashed during this trial and is not included in average and standard deviation.


372



1 1040.9 385.2 1426.1 73.0 27.0

2 1045.7 387 1432.7 73.0 27.0

3 1134.1 449.3 1583.4 71.6b 28.4b

4 1047.7 386.2 1433.9 73.1 26.9

5 1046.5 388.5 1435 72.9 27.1 Average 73.0 27.0

Standard Dev. 0.06 0.06

aAverage values from 220 and 230 nm: 73.0:27.0 and 72.9:27.1, respectively. bBaseline of chromatogram was problematic. Trial was not included in average and standard deviation.


373



1 4634.9 1198.5 5833.4 79.5 20.5

2 4609.1 1194.1 5803.2 79.4 20.6

3 4624 1195 5819 79.5 20.5

4 4627.8 1198.7 5826.5 79.4 20.6

5 4626.2 1199.1 5825.3 79.4 20.6 Average 79.4 20.6



374



1 14577.4 7477.6 22055 66.1 33.9

2 14411.2 7397.9 21809.1 66.1 33.9

3 14433.3 7407.8 21841.1 66.1 33.9

4 14477.2 7433.4 21910.6 66.1 33.9

5 14524.9 7458 21982.9 66.1 33.9 Average 66.1 33.9



375



1 11797.6 5764.7 17562.3 67.2 32.8

2 11791.3 5761.1 17552.4 67.2 32.8

3 11829.5 5781.8 17611.3 67.2 32.8

4 11931.2 5832.3 17763.5 67.2 32.8

5 11867.8 5801 17668.8 67.2 32.8 Average 67.2 32.8



376



1 1182.6 480 1662.6 71.1 28.9

2 1182.9 479.3 1662.2 71.2 28.8

3 1184 480.2 1664.2 71.1 28.9

4 1188.4 483.6 1672 71.1 28.9

5 1189.9 485.8 1675.7 71.0 29.0

Average 71.1 28.9


Catalyst (10 mol%) and H2O (50 µL)

377



1 7561.3 2613.2 10174.5 74.3 25.7

2 7584 2620.7 10204.7 74.3 25.7

3 7599.7 2625.6 10225.3 74.3 25.7

4 7606.2 2626.3 10232.5 74.3 25.7

5 7624.4 2636.8 10261.2 74.3 25.7 Average 74.3 25.7


Catalyst (10 mol%) and cocatalysts (10 mol%):

378



1 1546.2 564.7 2110.9 73.2 26.8

2 1555.3 567.3 2122.6 73.3 26.7

3 1558.9 569.7 2128.6 73.2 26.8

4 1557.6 569.3 2126.9 73.2 26.8

5 1559.9 569.1 2129 73.3 26.7 Average 73.3 26.7


Catalyst (10 mol%) and HCl (20 mol%) and NaBArF

4 (10 mol%):

379



1 4165.4 1627.2 5792.6 71.9 28.1

2 4177.4 1636.4 5813.8 71.9 28.1

3 0b 0b 0b - -

4 4604 1802.3 6406.3 71.9 28.1

5 4611.7 1802.9 6414.6 71.9 28.1 Average 71.9 28.1

SD 0.03 0.03 aAverage values from 220 and 230 nm: 71.8:28.2 and 71.7:28.3, respectively.

bComputer crashed during this trial and is not included in average and standard deviation.

Catalyst (10 mol%) and cocatalysts (20 mol%):

380

Purified Solvent. Reaction temperature = 0 °C. Five injections collected at 280 nm.a


1 4434.1 1277.1 5711.2 77.6 22.4

2 4435.3 1279.9 5715.2 77.6 22.4

3 4455.4 1281.9 5737.3 77.7 22.3

4 4468.3 1287 5755.3 77.6 22.4

5 4477.3 1289.7 5767 77.6 22.4 Average 77.6 22.4



381



1 8297.6 4998.8 13296.4 62.4 37.6

2 8342 5024.8 13366.8 62.4 37.6

3 8369.4 5031.7 13401.1 62.5 37.5

4 8406.8 5062.9 13469.7 62.4 37.6

5 8429.8 5077.2 13507 62.4 37.6 Average 62.4 37.6



382

Purified Solvent. Reaction temperature = 0 °C. Five injections collected at 280 nm.a


1 15538.4 4369.6 19908 78.1 21.9

2 15288.3 4307.6 19595.9 78.0 22.0

3 15301.6 4312.4 19614 78.0 22.0

4 15342.3 4324 19666.3 78.0 22.0

5 15355.7 4329.5 19685.2 78.0 22.0 Average 78.0 22.0



383



1 5059.3 2377.5 7436.8 68.0 32.0

2 5084.6 2393.7 7478.3 68.0 32.0

3 5110.8 2404.4 7515.2 68.0 32.0

4 5129.6 2413.2 7542.8 68.0 32.0

5 5147 2421.6 7568.6 68.0 32.0 Average 68.0 32.0



384

Oxa-Pictet-Spengler Chromatograms and Data Racemic

Solvent: DCM. Reaction temperature = rt. Five injections collected at 280 nm.a

catalyst system Trial Area (Peak 1) Area (Peak 2) Total Area % Area (Peak 1) % Area (Peak 2)

1 3613 3731.9 7344.9 49.2 50.8

2 3629.3 3750.5 7379.8 49.2 50.8

3 3627.7 3747.6 7375.3 49.2 50.8

4 3626.9 3742.3 7369.2 49.2 50.8

5 3625.9 3743.9 7369.8 49.2 50.8

Average 49.2 50.8



385


HCl (20 mol%)

1 2123.4 2150.7 4274.1 49.7 50.3

2 2124.9 2153.9 4278.8 49.7 50.3

3 2131.2 2162.9 4294.1 49.6 50.4

4 2133.2 2163.5 4296.7 49.6 50.4

5 2136.7 2168.3 4305 49.6 50.4

Average 49.7 50.3




1 3324.5 3468.8 6793.3 48.9 51.1

2 3327.9 3467.9 6795.8 49.0 51.0

3 3339.3 3483.9 6823.2 48.9 51.1

4 3341.3 3485.6 6826.9 48.9 51.1

5 3340.1 3482.2 6822.3 49.0 51.0 Average 48.9 51.1 Standard Dev. 0.01 0.01 aAverage values from 254 and 220 nm: 48.6:51.4 and 48.7:51.3, respectively.

Solvent: 50/50 DCM/ toluene. Reaction temperature = rt. Five injections collected at 280 nm.a

386


1 5532.7 5081.5 10614.2 52.1 47.9

2 5521.3 5082.1 10603.4 52.1 47.9

3 5514.7 5090.6 10605.3 52.0 48.0

4 5514.2 5109.2 10623.4 51.9 48.1




1 679 672.5 1351.5 50.2 49.8

2 705.8 694.4 1400.2 50.4 49.6

3 706 693.9 1399.9 50.4 49.6

4 708 699.4 1407.4 50.3 49.7

5 709.7 701.3 1411 50.3 49.7 Average 50.3 49.7 Standard Dev. 0.08 0.08 aAverage values from 254 and 220 nm: 49.8:50.2 and 50.3:49.7, respectively.


387


1 3351.9 3271 6622.9 50.6 49.4

2 2818.2 2747.4 5565.6 50.6 49.4

3 2831.8 2761.6 5593.4 50.6 49.4

4 2831.6 2759.9 5591.5 50.6 49.4




1 867.6 751.8 1619.4 53.6 46.4

2 868.7 754.7 1623.4 53.5 46.5

3 870.9 756.8 1627.7 53.5 46.5

4 872.6 756.1 1628.7 53.6 46.4


388



1 7315.3 7246.4 14561.7 50.2 49.8

2 7288.6 7219.5 14508.1 50.2 49.8

3 7306.4 7237 14543.4 50.2 49.8

4 7304 7233.2 14537.2 50.2 49.8




1 6017.9 6013.5 12031.4 50.0 50.0

2 6015.2 6008.6 12023.8 50.0 50.0

3 6052.7 6050.6 12103.3 50.0 50.0

4 6027.1 6023.9 12051 50.0 50.0

5 6041 6038 12079 50.0 50.0 Average 50.0 50.0 Standard Dev. 0.01 0.01 aAverage values from 254 and 220 nm: 49.6:50.4 and 49.6:50.4, respectively.

389

NMR Spectra 1H NMR in CD2Cl2 for 4.2

H2O

NMR Solvent

390

1H NMR in CD2Cl2 for ent-4.2

H2O

NMR Solvent

391

1H NMR in CDCl3 for 4.5

NMR Solvent

H2O

392

1H NMR in CDCl3 for ent-4.5

NMR Solvent

H2O

393

1H NMR in d6-DMSO for 4.8

NMR Solvent

394


NMR Solvent

395

References in Appendix for Chapter 4






396


X-ray Crystallography Data

REFERENCE NUMBER: 19163z

CRYSTAL STRUCTURE REPORT

C20H26IN3OS

397

A crystal (approximate dimensions 0.120 x 0.120 x 0.110 mm3) was placed onto the tip of

a 0.1 mm diameter glass capillary and mounted on a Bruker Photon-III diffractometer for

data collection at 125(2) K.1 A preliminary set of cell constants was calculated from

reflections harvested from three sets of frames. These initial sets of frames were oriented

such that orthogonal wedges of reciprocal space were surveyed. This produced an initial

orientation matrix determined from 9639 reflections. The data collection was carried out

using MoKα radiation (parabolic mirrors) with a frame time of 10 seconds and a detector

distance of 5.0 cm. A strategy program was used to assure complete coverage of all

unique data to a resolution of 0.69 Å. All major sections of frames were collected with

0.80º steps in ω or φ at different detector positions in 2θ. The intensity data were corrected

for absorption and decay (SADABS).2 Final cell constants were calculated from 9639

strong reflections from the actual data collection after integration (SAINT).3 Please refer

to Table 1 for additional crystal and refinement information.

Structure solution and refinement

The structure was solved using SHELXT 2014/5 (Sheldrick, 2014)4 and refined using

SHELXL-2018/3 (Sheldrick, 2018).4 The space group C2 was determined based on

systematic absences and intensity statistics. A direct-methods solution was calculated

which provided most non-hydrogen atoms from the E-map. Full-matrix least squares /

difference Fourier cycles were performed which located the remaining non-hydrogen

atoms. All non-hydrogen atoms were refined with anisotropic displacement parameters.

All hydrogen atoms were placed in ideal positions and refined as riding atoms with relative

isotropic displacement parameters. The final full matrix least squares refinement

converged to R1 = 0.0256 and wR2 = 0.0602 (F2, obs. data).

Structure description

The structure is the one suggested. Over several attempts, an unmodelable cluster of

electron density was found. Both crystallization solvents were attempted (acetonitrile and

diethyl ether). Therefore, the PLATON squeeze program was thus enlisted which found a

void space corresponding to one molecule of diethyl ether per asymmetric unit.

Data collection and structure solution were conducted at the X-Ray Crystallographic

Laboratory, 192 Kolthoff Hall, Department of Chemistry, University of Minnesota. All

calculations were performed using Pentium computers using the current SHELXTL suite

398

of programs. All publications arising from this report MUST either 1) include Victor G.

Young, Jr. and Brendan J. Graziano as a coauthor or 2) acknowledge Victor G. Young,

Jr., Brendan J. Graziano and the X-Ray Crystallographic Laboratory. The Bruker-AXS D8

Venture diffractometer was purchased through a grant from NSF/MRI (#1224900) and the

University of Minnesota.

________________________________________________________________

1 APEX2, Bruker Analytical X-ray Systems, Madison, WI (2004).

2 SADABS, Bruker Analytical X-ray Systems, Madison, WI (2004).

3 SAINT Bruker Analytical X-ray Systems, Madison, WI (2004).

4 SHELXTL 2013, Bruker Analytical X-Ray Systems, Madison, WI (2013); G. M.

Sheldrick, Acta Cryst. A64, 112-122 (2008).

7 A. L. Spek, Acta. Cryst. D65, 148-155 (2009). PLATON, A Multipurpose

Crystallographic Tool, Utrecht University, Utrecht, The Netherlands.

Some equations of interest:

Rint = |Fo2 -< Fo

2 >| / |Fo 2|

R1 = ||Fo|-|Fc|| / |Fo|

wR2 = [[w(Fo2-Fc

2)2] / [w(Fo2 )2]]1/2

where w = q / [2 (Fo2) + (a*P)2 + b*P + d + e*sin()]

GooF = S = [[w(Fo2-Fc

2)2] / (n-p)]1/2

399

Table S1. Crystal data and structure refinement for 19163z.

_______________________________________________________________

Identification code 19163

Empirical formula C20H26IN3OS

Formula weight 483.40

Temperature 125(2) K

Wavelength 0.71073 Å

Crystal system monoclinic

Space group C 2

Unit cell dimensions a = 26.913(4) Å α = 90°

b = 14.006(2) Å β = 112.300(5)°

c = 13.657(2) Å γ = 90°

Volume 4762.7(14) Å3

Z 8

Density (calculated) 1.348 Mg/m3

Absorption coefficient 1.444 mm-1

F(000) 1952

Crystal color, morphology colourless, block

Crystal size 0.120 x 0.120 x 0.110 mm3

Theta range for data collection 2.093 to 32.084°

Index ranges -40 ≤ h ≤ 40, -20 ≤ k ≤ 20, -20 ≤ l ≤ 20

Reflections collected 68674

Independent reflections 16605 [R(int) = 0.0274]

Observed reflections 15720

Completeness to theta = 25.242° 99.9%

Absorption correction Semi-empirical from equivalents

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 16605 / 1 / 495

Goodness-of-fit on F2 1.055

Final R indices [I>2sigma(I)] R1 = 0.0256, wR2 = 0.0602

R indices (all data) R1 = 0.0282, wR2 = 0.0615

Absolute structure parameter -0.012(4)

Extinction coefficient n/a

Largest diff. peak and hole 2.208 and -0.728 e.Å-3

400

Table S2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters

(Å2x 103 ) for 19163z. Ueq is defined as one third of the trace of the orthogonalized Uij

tensor.

___________________________________________________________________

x y z Ueq

___________________________________________________________________

I1 7539(1) 4860(1) 12442(1) 30(1)

S1 5833(1) 7496(1) 6543(1) 21(1)

O1 6846(1) 5670(2) 9777(2) 22(1)

N1 6696(1) 8353(2) 4607(2) 22(1)

C1 6662(2) 9408(2) 4521(3) 36(1)

I2 7677(1) 4795(1) 7688(1) 22(1)

S2 5782(1) 2185(1) 5737(1) 29(1)

O2 6885(1) 3983(2) 4131(2) 20(1)

N2 6679(1) 6516(2) 6490(2) 21(1)

C2 6772(1) 7836(2) 3843(2) 24(1)

N3 6374(1) 6031(2) 7735(2) 19(1)

C3 6827(1) 6859(2) 3944(2) 23(1)

N4 6580(1) 1293(2) 9010(2) 29(1)

C4 6792(1) 6414(2) 4825(2) 20(1)

N5 6652(1) 3076(2) 7119(2) 22(1)

C5 6700(1) 6964(2) 5592(2) 18(1)

N6 6386(1) 3571(2) 5425(2) 18(1)

C6 6663(1) 7945(2) 5476(2) 20(1)

C7 6308(1) 6654(2) 6948(2) 17(1)

C8 6032(1) 5959(2) 8338(2) 17(1)

C9 6336(1) 6133(2) 9552(2) 19(1)

C10 6010(1) 5544(2) 10056(2) 24(1)

C11 5781(1) 4739(2) 9284(2) 20(1)

C12 5572(1) 3872(2) 9441(2) 25(1)

C13 5377(1) 3237(2) 8595(3) 26(1)

C14 5387(1) 3467(2) 7610(2) 24(1)

C15 5598(1) 4337(2) 7460(2) 21(1)

401

C16 5795(1) 4966(2) 8302(2) 17(1)

C17 6415(1) 7190(2) 9910(2) 24(1)

C18 6661(2) 7228(3) 11132(3) 40(1)

C19 6793(2) 7697(2) 9480(3) 32(1)

C20 5879(2) 7740(3) 9538(3) 38(1)

C21 6463(2) 264(3) 9037(4) 50(1)

C22 6710(2) 1813(3) 9906(3) 30(1)

C23 6823(1) 2769(2) 9896(2) 28(1)

C24 6798(1) 3190(2) 8960(2) 23(1)

C25 6656(1) 2643(2) 8041(2) 20(1)

C26 6554(1) 1676(2) 8092(2) 25(1)

C27 6290(1) 2966(2) 6095(2) 19(1)

C28 6060(1) 3659(2) 4302(2) 18(1)

C29 6380(1) 3504(2) 3577(2) 17(1)

C30 6055(1) 4084(2) 2573(2) 20(1)

C31 5812(1) 4882(2) 2987(2) 18(1)

C32 5595(1) 5741(2) 2516(2) 21(1)

C33 5391(1) 6365(2) 3060(2) 23(1)

C34 5403(1) 6136(2) 4058(2) 23(1)

C35 5618(1) 5272(2) 4533(2) 21(1)

C36 5820(1) 4644(2) 3989(2) 17(1)

C37 6477(1) 2448(2) 3344(2) 22(1)

C38 6767(2) 2433(2) 2569(3) 35(1)

C39 6831(1) 1945(2) 4363(3) 29(1)

C40 5954(2) 1882(2) 2869(3) 37(1)

___________________________________________________________________

402

Table S3. Bond lengths [Å] and angles [°] for 19163z.

_____________________________________________________

S1-C7 1.672(3)

O1-C9 1.441(4)

O1-H1 0.71(4)

N1-C2 1.348(4)

N1-C6 1.349(3)

N1-C1 1.482(4)

C1-H1A 0.9800

C1-H1B 0.9800

C1-H1C 0.9800

S2-C27 1.672(3)

O2-C29 1.446(3)

O2-H2A 0.83(4)

N2-C7 1.377(4)

N2-C5 1.397(3)

N2-H2B 0.76(4)

C2-C3 1.378(4)

C2-H2 0.9500

N3-C7 1.343(3)

N3-C8 1.452(3)

N3-H3B 0.81(4)

C3-C4 1.390(4)

C3-H3 0.9500

N4-C26 1.341(4)

N4-C22 1.350(5)

N4-C21 1.479(4)

C4-C5 1.397(4)

C4-H4 0.9500

N5-C27 1.377(4)

N5-C25 1.393(3)

N5-H5BB 0.84(4)

C5-C6 1.382(4)

N6-C27 1.342(3)

403

N6-C28 1.456(3)

N6-H6B 0.82(4)

C6-H6 0.9500

C8-C16 1.523(4)

C8-C9 1.564(4)

C8-H8 1.0000

C9-C10 1.545(4)

C9-C17 1.548(4)

C10-C11 1.507(4)

C10-H10A 0.9900

C10-H10B 0.9900

C11-C12 1.389(4)

C11-C16 1.393(3)

C12-C13 1.393(4)

C12-H12 0.9500

C13-C14 1.393(4)

C13-H13 0.9500

C14-C15 1.392(4)

C14-H14 0.9500

C15-C16 1.385(4)

C15-H15 0.9500

C17-C19 1.529(5)

C17-C20 1.541(5)

C17-C18 1.546(4)

C18-H18A 0.9800

C18-H18B 0.9800

C18-H18C 0.9800

C19-H19A 0.9800

C19-H19B 0.9800

C19-H19C 0.9800

C20-H20A 0.9800

C20-H20B 0.9800

C20-H20C 0.9800

C21-H21A 0.9800

404

C21-H21B 0.9800

C21-H21C 0.9800

C22-C23 1.374(5)

C22-H22 0.9500

C23-C24 1.386(4)

C23-H23 0.9500

C24-C25 1.394(4)

C24-H24 0.9500

C25-C26 1.389(4)

C26-H26 0.9500

C28-C36 1.515(4)

C28-C29 1.553(4)

C28-H28 1.0000

C29-C30 1.548(4)

C29-C37 1.557(4)

C30-C31 1.508(4)

C30-H30A 0.9900

C30-H30B 0.9900

C31-C32 1.384(4)

C31-C36 1.400(3)

C32-C33 1.389(4)

C32-H32 0.9500

C33-C34 1.389(4)

C33-H33 0.9500

C34-C35 1.391(4)

C34-H34 0.9500

C35-C36 1.388(4)

C35-H35 0.9500

C37-C39 1.528(4)

C37-C40 1.530(5)

C37-C38 1.535(4)

C38-H38A 0.9800

C38-H38B 0.9800

C38-H38C 0.9800

405

C39-H39A 0.9800

C39-H39B 0.9800

C39-H39C 0.9800

C40-H40A 0.9800

C40-H40B 0.9800

C40-H40C 0.9800

C9-O1-H1 107(3)

C2-N1-C6 122.2(3)

C2-N1-C1 119.7(3)

C6-N1-C1 118.1(3)

N1-C1-H1A 109.5

N1-C1-H1B 109.5

H1A-C1-H1B 109.5

N1-C1-H1C 109.5

H1A-C1-H1C 109.5

H1B-C1-H1C 109.5

C29-O2-H2A 107(3)

C7-N2-C5 127.8(2)

C7-N2-H2B 111(3)

C5-N2-H2B 120(3)

N1-C2-C3 119.9(3)

N1-C2-H2 120.1

C3-C2-H2 120.1

C7-N3-C8 125.4(2)

C7-N3-H3B 115(3)

C8-N3-H3B 118(3)

C2-C3-C4 119.4(3)

C2-C3-H3 120.3

C4-C3-H3 120.3

C26-N4-C22 122.3(3)

C26-N4-C21 118.5(3)

C22-N4-C21 119.2(3)

C3-C4-C5 119.5(3)

406

C3-C4-H4 120.3

C5-C4-H4 120.3

C27-N5-C25 129.0(2)

C27-N5-H5BB 121(3)

C25-N5-H5BB 109(3)

C6-C5-C4 119.1(2)

C6-C5-N2 121.5(3)

C4-C5-N2 119.2(2)

C27-N6-C28 125.2(2)

C27-N6-H6B 116(3)

C28-N6-H6B 119(3)

N1-C6-C5 119.8(3)

N1-C6-H6 120.1

C5-C6-H6 120.1

N3-C7-N2 112.0(2)

N3-C7-S1 125.1(2)

N2-C7-S1 122.92(19)

N3-C8-C16 113.1(2)

N3-C8-C9 113.6(2)

C16-C8-C9 102.8(2)

N3-C8-H8 109.0

C16-C8-H8 109.0

C9-C8-H8 109.0

O1-C9-C10 108.7(2)

O1-C9-C17 110.9(2)

C10-C9-C17 113.8(2)

O1-C9-C8 103.2(2)

C10-C9-C8 103.4(2)

C17-C9-C8 116.0(2)

C11-C10-C9 103.8(2)

C11-C10-H10A 111.0

C9-C10-H10A 111.0

C11-C10-H10B 111.0

C9-C10-H10B 111.0

407

H10A-C10-H10B 109.0

C12-C11-C16 120.6(3)

C12-C11-C10 128.9(2)

C16-C11-C10 110.5(2)

C11-C12-C13 118.4(3)

C11-C12-H12 120.8

C13-C12-H12 120.8

C14-C13-C12 121.0(3)

C14-C13-H13 119.5

C12-C13-H13 119.5

C15-C14-C13 120.2(3)

C15-C14-H14 119.9

C13-C14-H14 119.9

C16-C15-C14 118.9(3)

C16-C15-H15 120.6

C14-C15-H15 120.6

C15-C16-C11 120.8(3)

C15-C16-C8 129.2(2)

C11-C16-C8 110.0(2)

C19-C17-C20 108.5(3)

C19-C17-C18 108.9(3)

C20-C17-C18 107.6(3)

C19-C17-C9 110.8(3)

C20-C17-C9 112.0(3)

C18-C17-C9 109.0(2)

C17-C18-H18A 109.5

C17-C18-H18B 109.5

H18A-C18-H18B 109.5

C17-C18-H18C 109.5

H18A-C18-H18C 109.5

H18B-C18-H18C 109.5

C17-C19-H19A 109.5

C17-C19-H19B 109.5

H19A-C19-H19B 109.5

408

C17-C19-H19C 109.5

H19A-C19-H19C 109.5

H19B-C19-H19C 109.5

C17-C20-H20A 109.5

C17-C20-H20B 109.5

H20A-C20-H20B 109.5

C17-C20-H20C 109.5

H20A-C20-H20C 109.5

H20B-C20-H20C 109.5

N4-C21-H21A 109.5

N4-C21-H21B 109.5

H21A-C21-H21B 109.5

N4-C21-H21C 109.5

H21A-C21-H21C 109.5

H21B-C21-H21C 109.5

N4-C22-C23 119.9(3)

N4-C22-H22 120.0

C23-C22-H22 120.0

C22-C23-C24 119.3(3)

C22-C23-H23 120.3

C24-C23-H23 120.3

C23-C24-C25 119.9(3)

C23-C24-H24 120.1

C25-C24-H24 120.1

C26-C25-N5 122.4(3)

C26-C25-C24 118.8(3)

N5-C25-C24 118.7(3)

N4-C26-C25 119.7(3)

N4-C26-H26 120.1

C25-C26-H26 120.1

N6-C27-N5 112.1(2)

N6-C27-S2 124.2(2)

N5-C27-S2 123.7(2)

N6-C28-C36 113.4(2)

409

N6-C28-C29 113.7(2)

C36-C28-C29 103.1(2)

N6-C28-H28 108.8

C36-C28-H28 108.8

C29-C28-H28 108.8

O2-C29-C30 108.8(2)

O2-C29-C28 103.9(2)

C30-C29-C28 103.2(2)

O2-C29-C37 110.5(2)

C30-C29-C37 113.6(2)

C28-C29-C37 116.1(2)

C31-C30-C29 103.7(2)

C31-C30-H30A 111.0

C29-C30-H30A 111.0

C31-C30-H30B 111.0

C29-C30-H30B 111.0

H30A-C30-H30B 109.0

C32-C31-C36 120.5(2)

C32-C31-C30 129.5(2)

C36-C31-C30 110.0(2)

C31-C32-C33 118.8(3)

C31-C32-H32 120.6

C33-C32-H32 120.6

C34-C33-C32 120.9(3)

C34-C33-H33 119.6

C32-C33-H33 119.6

C33-C34-C35 120.6(3)

C33-C34-H34 119.7

C35-C34-H34 119.7

C36-C35-C34 118.7(2)

C36-C35-H35 120.7

C34-C35-H35 120.7

C35-C36-C31 120.6(2)

C35-C36-C28 129.6(2)

410

C31-C36-C28 109.8(2)

C39-C37-C40 107.7(3)

C39-C37-C38 108.5(3)

C40-C37-C38 109.1(3)

C39-C37-C29 110.3(2)

C40-C37-C29 112.3(2)

C38-C37-C29 108.8(2)

C37-C38-H38A 109.5

C37-C38-H38B 109.5

H38A-C38-H38B 109.5

C37-C38-H38C 109.5

H38A-C38-H38C 109.5

H38B-C38-H38C 109.5

C37-C39-H39A 109.5

C37-C39-H39B 109.5

H39A-C39-H39B 109.5

C37-C39-H39C 109.5

H39A-C39-H39C 109.5

H39B-C39-H39C 109.5

C37-C40-H40A 109.5

C37-C40-H40B 109.5

H40A-C40-H40B 109.5

C37-C40-H40C 109.5

H40A-C40-H40C 109.5

H40B-C40-H40C 109.5

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:

411

Table S4. Anisotropic displacement parameters (Å2x 103) for 19163z. The anisotropic

displacement factor exponent takes the form:

-2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

__________________________________________________________________

U11 U22 U33 U23 U13 U12

__________________________________________________________________

I1 32(1) 34(1) 24(1) 9(1) 11(1) 1(1)

S1 21(1) 22(1) 23(1) 6(1) 9(1) 2(1)

O1 25(1) 25(1) 16(1) 4(1) 8(1) 2(1)

N1 30(1) 20(1) 19(1) 4(1) 11(1) -3(1)

C1 62(2) 21(1) 30(2) 6(1) 22(2) -4(2)

I2 25(1) 17(1) 25(1) 1(1) 11(1) 0(1)

S2 28(1) 34(1) 25(1) 3(1) 10(1) -12(1)

O2 21(1) 23(1) 18(1) 1(1) 9(1) -2(1)

N2 23(1) 22(1) 20(1) 8(1) 11(1) 3(1)

C2 31(1) 28(1) 16(1) 2(1) 11(1) -3(1)

N3 19(1) 20(1) 18(1) 6(1) 9(1) 2(1)

C3 26(1) 28(1) 18(1) -2(1) 12(1) -4(1)

N4 47(2) 22(1) 28(1) 9(1) 24(1) 6(1)

C4 19(1) 21(1) 20(1) 3(1) 9(1) -1(1)

N5 24(1) 24(1) 18(1) 5(1) 6(1) -4(1)

C5 17(1) 21(1) 15(1) 3(1) 6(1) -3(1)

N6 19(1) 22(1) 13(1) 3(1) 6(1) -3(1)

C6 25(1) 19(1) 17(1) 1(1) 10(1) -5(1)

C7 18(1) 16(1) 15(1) 2(1) 6(1) -3(1)

C8 20(1) 18(1) 15(1) 2(1) 10(1) -1(1)

C9 24(1) 20(1) 16(1) 1(1) 10(1) -1(1)

C10 31(1) 27(1) 18(1) 0(1) 14(1) -4(1)

C11 22(1) 22(1) 18(1) 5(1) 10(1) -2(1)

C12 27(1) 27(1) 25(1) 7(1) 13(1) -4(1)

C13 21(1) 23(1) 33(2) 3(1) 9(1) -6(1)

C14 18(1) 25(1) 27(1) -3(1) 7(1) -2(1)

C15 19(1) 25(1) 18(1) 1(1) 6(1) 0(1)

C16 18(1) 18(1) 16(1) 2(1) 8(1) 0(1)

412

C17 33(2) 19(1) 21(1) -1(1) 10(1) -1(1)

C18 65(3) 27(2) 22(1) -6(1) 12(2) -9(2)

C19 41(2) 22(1) 34(2) -3(1) 16(2) -10(1)

C20 46(2) 27(2) 47(2) -2(1) 23(2) 10(1)

C21 98(4) 23(2) 46(2) 11(2) 48(3) 2(2)

C22 40(2) 34(2) 23(1) 9(1) 19(1) 5(1)

C23 32(2) 33(2) 18(1) 4(1) 9(1) 2(1)

C24 21(1) 27(1) 20(1) 5(1) 6(1) 0(1)

C25 21(1) 23(1) 18(1) 7(1) 8(1) 3(1)

C26 39(2) 22(1) 22(1) 6(1) 19(1) 5(1)

C27 20(1) 22(1) 18(1) 4(1) 9(1) 1(1)

C28 18(1) 20(1) 14(1) 3(1) 4(1) 1(1)

C29 18(1) 17(1) 16(1) 1(1) 7(1) 1(1)

C30 24(1) 22(1) 13(1) 2(1) 7(1) 6(1)

C31 19(1) 19(1) 16(1) -1(1) 7(1) 3(1)

C32 21(1) 23(1) 19(1) 2(1) 8(1) 4(1)

C33 21(1) 23(1) 24(1) 2(1) 8(1) 6(1)

C34 20(1) 28(1) 22(1) -4(1) 8(1) 5(1)

C35 19(1) 30(1) 14(1) -1(1) 7(1) 1(1)

C36 16(1) 21(1) 15(1) 0(1) 6(1) 1(1)

C37 25(1) 17(1) 23(1) 0(1) 6(1) 4(1)

C38 52(2) 27(2) 34(2) -1(1) 25(2) 12(1)

C39 31(2) 20(1) 33(2) 4(1) 9(1) 8(1)

C40 32(2) 21(1) 47(2) -7(1) 2(2) -1(1)

___________________________________________________________________

413

Table S5. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x

103) for 19163z.

___________________________________________________________________

x y z U(eq)

___________________________________________________________________

H1 6957(17) 5570(30) 10330(30) 27

H1A 6831 9691 5227 54

H1B 6285 9602 4206 54

H1C 6850 9627 4072 54

H2A 6990(16) 4190(30) 3670(30) 24

H2B 6871(17) 6110(30) 6760(30) 25

H2 6787 8145 3236 29

H3B 6665(16) 5770(30) 7960(30) 22

H3 6889 6493 3416 28

H4 6830 5741 4905 23

H5BB 6875(17) 3530(30) 7280(30) 27

H6B 6665(16) 3880(30) 5670(30) 22

H6 6616 8331 6006 24

H8 5733 6432 8056 20

H10A 6244 5297 10759 29

H10B 5720 5933 10135 29

H12 5561 3715 10110 30

H13 5236 2639 8691 32

H14 5249 3029 7039 29

H15 5608 4495 6791 25

H18A 6714 7896 11365 59

H18B 7007 6895 11392 59

H18C 6416 6919 11414 59

H19A 6893 8322 9822 48

H19B 6612 7784 8714 48

H19C 7117 7311 9629 48

H20A 5942 8389 9827 57

H20B 5628 7410 9787 57

H20C 5726 7770 8763 57

414

H21A 6589 -82 8551 74

H21B 6075 171 8820 74

H21C 6648 20 9757 74

H22 6723 1518 10541 36

H23 6917 3137 10525 33

H24 6877 3849 8945 28

H26 6467 1287 7479 30

H28 5762 3181 4110 21

H30A 6292 4339 2231 24

H30B 5772 3687 2056 24

H32 5586 5900 1834 25

H33 5240 6956 2745 28

H34 5262 6573 4420 28

H35 5626 5114 5216 25

H38A 6832 1770 2419 52

H38B 7111 2769 2884 52

H38C 6544 2750 1909 52

H39A 6958 1336 4189 43

H39B 6623 1826 4804 43

H39C 7141 2350 4751 43

H40A 6034 1224 2731 56

H40B 5722 2181 2203 56

H40C 5771 1878 3366 56

__________________________________________________________________

415

Table S6. Torsion angles [°] for 19163z.

_________________________________________________________________

C6-N1-C2-C3 -0.9(5)

C1-N1-C2-C3 177.1(3)

N1-C2-C3-C4 1.4(5)

C2-C3-C4-C5 0.2(4)

C3-C4-C5-C6 -2.2(4)

C3-C4-C5-N2 -178.3(3)

C7-N2-C5-C6 49.3(4)

C7-N2-C5-C4 -134.7(3)

C2-N1-C6-C5 -1.2(4)

C1-N1-C6-C5 -179.2(3)

C4-C5-C6-N1 2.7(4)

N2-C5-C6-N1 178.7(3)

C8-N3-C7-N2 -176.7(2)

C8-N3-C7-S1 2.6(4)

C5-N2-C7-N3 173.3(3)

C5-N2-C7-S1 -6.0(4)

C7-N3-C8-C16 123.4(3)

C7-N3-C8-C9 -119.9(3)

N3-C8-C9-O1 -38.7(3)

C16-C8-C9-O1 83.9(2)

N3-C8-C9-C10 -152.0(2)

C16-C8-C9-C10 -29.3(3)

N3-C8-C9-C17 82.7(3)

C16-C8-C9-C17 -154.6(2)

O1-C9-C10-C11 -80.0(3)

C17-C9-C10-C11 155.9(2)

C8-C9-C10-C11 29.2(3)

C9-C10-C11-C12 162.0(3)

C9-C10-C11-C16 -18.5(3)

C16-C11-C12-C13 0.0(4)

C10-C11-C12-C13 179.5(3)

C11-C12-C13-C14 -0.6(5)

416

C12-C13-C14-C15 0.8(5)

C13-C14-C15-C16 -0.3(4)

C14-C15-C16-C11 -0.2(4)

C14-C15-C16-C8 -178.4(3)

C12-C11-C16-C15 0.4(4)

C10-C11-C16-C15 -179.1(2)

C12-C11-C16-C8 178.9(3)

C10-C11-C16-C8 -0.6(3)

N3-C8-C16-C15 -39.5(4)

C9-C8-C16-C15 -162.5(3)

N3-C8-C16-C11 142.1(2)

C9-C8-C16-C11 19.2(3)

O1-C9-C17-C19 50.6(3)

C10-C9-C17-C19 173.5(3)

C8-C9-C17-C19 -66.7(3)

O1-C9-C17-C20 171.9(3)

C10-C9-C17-C20 -65.2(3)

C8-C9-C17-C20 54.6(3)

O1-C9-C17-C18 -69.2(3)

C10-C9-C17-C18 53.7(4)

C8-C9-C17-C18 173.5(3)

C26-N4-C22-C23 -0.2(5)

C21-N4-C22-C23 179.6(4)

N4-C22-C23-C24 0.5(5)

C22-C23-C24-C25 0.3(5)

C27-N5-C25-C26 44.0(5)

C27-N5-C25-C24 -139.8(3)

C23-C24-C25-C26 -1.5(4)

C23-C24-C25-N5 -177.8(3)

C22-N4-C26-C25 -1.0(5)

C21-N4-C26-C25 179.3(4)

N5-C25-C26-N4 177.9(3)

C24-C25-C26-N4 1.8(5)

C28-N6-C27-N5 -177.0(2)

417

C28-N6-C27-S2 1.6(4)

C25-N5-C27-N6 173.8(3)

C25-N5-C27-S2 -4.8(5)

C27-N6-C28-C36 119.3(3)

C27-N6-C28-C29 -123.4(3)

N6-C28-C29-O2 -40.1(3)

C36-C28-C29-O2 83.0(2)

N6-C28-C29-C30 -153.6(2)

C36-C28-C29-C30 -30.5(2)

N6-C28-C29-C37 81.4(3)

C36-C28-C29-C37 -155.4(2)

O2-C29-C30-C31 -79.9(3)

C28-C29-C30-C31 30.0(3)

C37-C29-C30-C31 156.5(2)

C29-C30-C31-C32 162.3(3)

C29-C30-C31-C36 -18.6(3)

C36-C31-C32-C33 0.6(4)

C30-C31-C32-C33 179.6(3)

C31-C32-C33-C34 0.0(4)

C32-C33-C34-C35 -0.3(5)

C33-C34-C35-C36 0.0(4)

C34-C35-C36-C31 0.6(4)

C34-C35-C36-C28 -178.1(3)

C32-C31-C36-C35 -0.9(4)

C30-C31-C36-C35 179.9(2)

C32-C31-C36-C28 178.0(2)

C30-C31-C36-C28 -1.1(3)

N6-C28-C36-C35 -37.5(4)

C29-C28-C36-C35 -160.9(3)

N6-C28-C36-C31 143.6(2)

C29-C28-C36-C31 20.3(3)

O2-C29-C37-C39 53.6(3)

C30-C29-C37-C39 176.2(2)

C28-C29-C37-C39 -64.4(3)

418

O2-C29-C37-C40 173.7(3)

C30-C29-C37-C40 -63.7(3)

C28-C29-C37-C40 55.7(3)

O2-C29-C37-C38 -65.4(3)

C30-C29-C37-C38 57.2(3)

C28-C29-C37-C38 176.7(3)

___________________________________________________________________


Table S7. Hydrogen bonds for 19163z [Å and °].

___________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

___________________________________________________________________

O1-H1...I1 0.71(4) 2.88(4) 3.586(2) 168(4)

O2-H2A...I1#1 0.83(4) 2.79(4) 3.607(2) 169(4)

N2-H2B...I2 0.76(4) 2.76(4) 3.516(3) 172(4)

N3-H3B...I2 0.81(4) 3.19(4) 3.933(2) 153(3)

N5-H5BB...I2 0.84(4) 2.69(4) 3.520(3) 172(4)

N6-H6B...I2 0.82(4) 3.31(4) 4.050(2) 152(3)

__________________________________________________________________


#1 x,y,z-1

419

Important Structural Measurements

In the cif file, 2 thioureas and 2 iodides are present. One thiourea is hidden each of the

pictures below to provide clarity.

Thiourea 1

Thiourea 1 Important Hydrogen Bond Lengths

Atoms Length (Å)

H3B to I2 3.204

H2B to I2 2.756

H1 to I1 2.887

H3B to O1 2.342

Thiourea 1 Important Hydrogen Bond Angles

Atoms Angle (°)

N2-H2B-I2 172.30

N3-H3B-I2 152.81

O1-H1-I1 167.50

N3-H3B-O1 102.75

420

Thiourea 1 Dihedral Angles and Torsion angles about the thiourea moiety

Atoms Dihedral/Torsion Angle (°)

H2B-N2-C7-N3 1.32

H3B-N3-C7-N2 17.45

C6-C5-N2-C7 49.32

C4-C5-N2-C7 45.33

C9-C8-N3-C7 60.14

C16-C8-N3-C7 123.45

C8-N3-C7-N2 176.72

C5-N2-C7-N3 173.28

Thiourea 2

Thiourea 2 Important Hydrogen Bond Lengths

Atoms Length (Å)

H6B to I2 3.310

H5BB to I2 2.694

H23 to I1 3.486

H6B to O2 2.394

421

Thiourea 2 Important Hydrogen Bond Angles

Atoms Angle (°)

N5-H5BB-I2 172.19

N6-H6B-I2 151.75

C23-H23-I1 160.43

N6-H6B-O2 99.57

Thiourea 2 Dihedral Angles and Torsion angles about the thiourea moiety

Atoms Dihedral/Torsion Angle (°)

H5BB-N5-C27-N6 6.58

H6B-N6-C27-N5 7.94

C26-C25-N5-C27 44.07

C24-C25-N5-C27 40.20

C29-C28-N6-C27 56.61

C36-C28-N6-C27 119.25

C28-N6-C27-N5 177.02

C25-N5-C27-N6 173.85

422

NMR Spectra


DCM

423

13C NMR in CDCl3 for 5.10

NMR solvent

424

1H NMR in C6D6 for 5.12

NMR solvent

425

13C NMR in C6D6 for 5.12

NMR solvent

426


NMR solvent

427


NMR solvent

428

1H NMR in CD2Cl2 for 5.15

NMR solvent

429

13C NMR in CD2Cl2 for 5.15

NMR solvent

430


NMR solvent

431


NMR solvent

432


NMR solvent

433


NMR solvent

434


NMR Solvent

H2O

435


NMR Solvent

436


NMR Solvent H2O

437


NMR Solvent

438


NMR Solvent

H2O

439


NMR Solvent

440


NMR Solvent DCM

441


NMR Solvent

442


NMR Solvent

443


NMR Solvent

444

19F NMR in CD2Cl2 for 5.22

Fluorobenzene

445


NMR Solvent

H2O

446


NMR Solvent

447

1H NMR in CD3CN for 5.3

NMR Solvent

H2O

448


NMR Solvent

449


Fluorobenzene

450

HPLC Chromatograms and Data1

Oxazolidinones Racemic on RegisPack Analytical Column for 5.15

451

Racemic on WhelkO1 Semi-Preparative Column for 5.6

Racemic on RegisPack Analytical Column for 5.6

452

First enantiomer from Semi-prep HPLC (on RegisPack analytical column) for 5.6

Five injections collected at 220 nm.a


1 757.9 5.7 763.6 99.3 0.7

2 756.8 4.1 760.9 99.5 0.5

3 770.7 3.7 774.4 99.5 0.5

4 764.8 3.2 768 99.6 0.4


aAverage values from 250 and 220 nm: 99.3:0.7 and 99.5:0.5, respectively.

453

Second enantiomer from Semi-prep HPLC (on RegisPack analytical column) for 5.6



1 11 454.2 465.2 2.4 97.6

2 9.6 461.6 471.2 2.0 98.0

3 10.9 462.7 473.6 2.3 97.7

4 8.4 459.3 467.7 1.8 98.2



454

Chromatograms of Friedel-Crafts reactions2



1 5101.4 3098.1 8199.5 62.2 37.8

2 5086.9 3093.8 8180.7 62.2 37.8

3 5108.9 3102.9 8211.8 62.2 37.8

4 5129.4 3115.2 8244.6 62.2 37.8

5 5126.6 3115.5 8242.1 62.2 37.8

Average 62.2 37.8


Catalyst (10 mol%):

455



1 11099.4 2848.5 13947.9 79.6 20.4

2 11076 2842.7 13918.7 79.6 20.4

3 11118.9 2853.3 13972.2 79.6 20.4

4 11144.5 2860.5 14005 79.6 20.4

5 11179.9 2868.2 14048.1 79.6 20.4

Average 79.6 20.4



456

Catalyst (10 mol%):


457



1 1888.5 8093.2 9981.7 18.9 81.1

2 1895.4 8096 9991.4 19.0 81.0

3 1917.2 8118.9 10036.1 19.1 80.9

4 1915.7 8166 10081.7 19.0 81.0



Catalyst and cocatalyst (10 mol%):

458



1 3388.8 1970 5358.8 63.2 36.8

2 3392.6 1969.9 5362.5 63.3 36.7

3 3408.2 1980.4 5388.6 63.2 36.8

4 3410.2 1981.5 5391.7 63.2 36.8

5 3418.6 1988.6 5407.2 63.2 36.8

Average 63.2 36.8



459



1 7972.6 5379.4 13352 59.7 40.3

2 7993.9 5394.2 13388.1 59.7 40.3

3 8046.6 5424.8 13471.4 59.7 40.3

4 8016.2 5407.9 13424.1 59.7 40.3




460



1 7443.5 7744.4 15187.9 49.0 51.0

2 7485.6 7790 15275.6 49.0 51.0

3 7504.2 7807.8 15312 49.0 51.0

4 7539 7846.4 15385.4 49.0 51.0

5 7563.7 7870.3 15434 49.0 51.0 Average 49.0 51.0 Standard Dev. 0.00 0.00



461



1 2794.7 784.4 3579.1 78.1 21.9

2 2796.1 780.2 3576.3 78.2 21.8

3 2825.6 789.4 3615 78.2 21.8

4 2794.8 779.1 3573.9 78.2 21.8

5 2805.5 784.5 3590 78.1 21.9 Average 78.2 21.8 Standard Dev. 0.04 0.04



462



1 2408.1 3736.1 6144.2 39.2 60.8

2 2392.3 3708.8 6101.1 39.2 60.8

3 2398.8 3722.2 6121 39.2 60.8

4 2393.8 3712.4 6106.2 39.2 60.8




463

Computational Data for Thioureas 5.2 R = H; TS(S) E = -2754.094709, ZPE = 0.576094, TC = 0.617566, S = 251.547, imag. freq. = -390 cm–1 1 7 0 -0.764092 2.263118 -0.246867 2 6 0 -2.035157 1.917245 0.027720 3 16 0 -3.167764 2.978103 0.684703 4 7 0 -2.267620 0.596744 -0.257701 5 1 0 -1.427657 0.015997 -0.194031 6 1 0 -0.152360 1.557399 -0.669211 7 1 0 2.572460 1.619943 1.192374 8 7 0 3.348905 1.082019 0.779590 9 6 0 3.632991 1.046369 -0.511452 10 6 0 4.527292 -0.032126 -0.767753 11 1 0 3.139939 1.707666 -1.209122 12 1 0 5.121665 -0.090459 -1.668012 13 8 0 0.224881 -0.564633 0.625907 14 7 0 1.130066 -0.571195 -0.266162 15 8 0 1.077328 0.277599 -1.197653 16 6 0 2.134254 -1.461474 -0.211400 17 1 0 2.108698 -2.114626 0.643908 18 8 0 0.986819 2.000917 1.876166 19 1 0 0.362550 1.306486 1.608559 20 6 0 -0.107094 3.452789 0.238557 21 6 0 0.437672 3.302112 1.685716 22 1 0 -0.812154 4.287885 0.206557 23 6 0 1.143411 3.776344 -0.547132 24 6 0 1.615397 4.281436 1.734560 25 1 0 -0.330557 3.495145 2.436238 26 6 0 2.132768 4.253755 0.312311 27 6 0 1.366381 3.665993 -1.912289 28 1 0 1.262584 5.284378 1.992265 29 1 0 2.352605 3.980074 2.481234 30 6 0 3.373126 4.626250 -0.188974 31 1 0 0.592640 3.286103 -2.570656 32 6 0 2.610538 4.045571 -2.416212 33 1 0 4.151537 4.987966 0.473469 34 6 0 3.604885 4.519331 -1.560504 35 1 0 2.808304 3.965900 -3.478440 36 1 0 4.569328 4.802618 -1.965119 37 6 0 -3.474331 -0.103132 -0.136187 38 6 0 -3.432670 -1.385115 0.407197 39 6 0 -4.688331 0.408073 -0.600071 40 6 0 -4.596906 -2.138155 0.498765 41 1 0 -2.487031 -1.785567 0.758454 42 6 0 -5.837394 -0.357702 -0.482053 43 1 0 -4.728028 1.390713 -1.047863 44 6 0 -5.814173 -1.635283 0.067295

464

45 6 0 -4.514427 -3.497585 1.128654 46 6 0 -7.127096 0.178317 -1.032981 47 1 0 -6.720410 -2.220213 0.150143 48 9 0 -5.628278 -4.213765 0.940119 49 9 0 -3.491433 -4.210597 0.635411 50 9 0 -4.318453 -3.416573 2.454241 51 9 0 -8.190786 -0.304143 -0.377300 52 9 0 -7.287116 -0.154681 -2.324839 53 9 0 -7.186780 1.513811 -0.968427 54 6 0 3.139739 -1.430534 -1.215237 55 1 0 2.824569 -0.947897 -2.134006 56 6 0 4.005875 -2.617042 -1.422117 57 6 0 4.208417 -3.582895 -0.431654 58 6 0 4.652930 -2.764300 -2.653653 59 6 0 5.034108 -4.674747 -0.674742 60 1 0 3.731293 -3.486141 0.535895 61 6 0 5.481226 -3.851280 -2.893957 62 1 0 4.500442 -2.017906 -3.426795 63 6 0 5.674135 -4.810415 -1.902198 64 1 0 5.180078 -5.418405 0.099386 65 1 0 5.972219 -3.953996 -3.854034 66 1 0 6.318892 -5.660910 -2.088157 67 6 0 4.142106 0.164129 1.483082 68 6 0 4.967533 -0.480100 0.551976 69 6 0 4.183481 -0.101794 2.844765 70 6 0 5.891895 -1.424179 0.992307 71 6 0 5.112304 -1.045736 3.265951 72 1 0 3.523920 0.403904 3.538840 73 6 0 5.959731 -1.690537 2.355355 74 1 0 6.540218 -1.935492 0.290574 75 1 0 5.186498 -1.282166 4.320215 76 1 0 6.679280 -2.411746 2.723436 R = H; TS(R) E = -2754.091657, ZPE = 0.576472, TC = 0.617981, S = 251.802, imag. freq. = -398 cm–1 1 7 0 0.597980 -2.564547 -0.299583 2 6 0 1.863980 -2.162151 -0.074103 3 16 0 2.950876 -3.026969 0.884195 4 7 0 2.147705 -0.979631 -0.694044 5 1 0 1.327957 -0.484722 -1.051443 6 1 0 -0.011043 -1.905656 -0.788811 7 1 0 -2.656809 -1.693406 0.905872 8 7 0 -3.205656 -0.833662 0.937399 9 6 0 -2.942998 0.119873 1.815323 10 1 0 -2.165794 -0.010281 2.551715 11 8 0 -0.956236 -2.063416 1.929479 12 1 0 -0.328737 -1.425265 1.553265

465

13 6 0 -0.041436 -3.681286 0.357865 14 6 0 -0.456279 -3.388779 1.827116 15 1 0 0.634580 -4.541345 0.340608 16 6 0 -1.365271 -4.027061 -0.286174 17 6 0 -1.647102 -4.324036 2.062623 18 1 0 0.368165 -3.541550 2.524474 19 6 0 -2.284798 -4.404433 0.693749 20 6 0 -1.709094 -4.017810 -1.630132 21 1 0 -1.297565 -5.310747 2.380780 22 1 0 -2.310582 -3.932379 2.835325 23 6 0 -3.569226 -4.789816 0.334118 24 1 0 -0.990837 -3.714454 -2.384329 25 6 0 -2.998030 -4.411173 -1.991245 26 1 0 -4.291590 -5.079929 1.088977 27 6 0 -3.917488 -4.796461 -1.017353 28 1 0 -3.287475 -4.413050 -3.035508 29 1 0 -4.917016 -5.094205 -1.312235 30 6 0 3.282228 -0.176683 -0.478217 31 6 0 3.084692 1.151820 -0.117111 32 6 0 4.577371 -0.660832 -0.667407 33 6 0 4.180440 1.992199 0.048382 34 1 0 2.075042 1.512671 0.052720 35 6 0 5.653316 0.190975 -0.475300 36 1 0 4.730356 -1.686383 -0.971493 37 6 0 5.473388 1.524551 -0.119321 38 6 0 3.928915 3.429958 0.396137 39 6 0 7.052362 -0.332877 -0.620981 40 1 0 6.322600 2.181606 0.016412 41 9 0 5.040857 4.058892 0.792590 42 9 0 3.442188 4.114060 -0.651410 43 9 0 3.026762 3.550337 1.381276 44 9 0 7.870164 0.581837 -1.161973 45 9 0 7.107889 -1.424778 -1.392243 46 9 0 7.581577 -0.665722 0.566809 47 6 0 -3.734343 1.264210 1.524794 48 1 0 -3.925422 2.032203 2.260204 49 6 0 -2.376592 2.242259 0.413938 50 6 0 -1.937268 1.416149 -0.652641 51 1 0 -1.649989 2.358935 1.211164 52 7 0 -0.937722 0.539060 -0.459680 53 1 0 -2.360536 1.390900 -1.641936 54 8 0 -0.556516 -0.186090 -1.430632 55 8 0 -0.368449 0.427790 0.659223 56 6 0 -3.134785 3.480847 0.101023 57 6 0 -3.143022 4.518395 1.039001 58 6 0 -3.840194 3.644375 -1.094799 59 6 0 -3.834602 5.695360 0.787594 60 1 0 -2.598129 4.398910 1.969988

466

61 6 0 -4.530520 4.824450 -1.346939 62 1 0 -3.861639 2.853053 -1.833498 63 6 0 -4.530966 5.850876 -0.408531 64 1 0 -3.826673 6.492566 1.520824 65 1 0 -5.068770 4.940020 -2.279856 66 1 0 -5.068851 6.769676 -0.608623 67 6 0 -4.277219 -0.464345 0.112687 68 6 0 -4.695791 0.810736 0.521216 69 6 0 -4.882057 -1.168390 -0.919109 70 6 0 -5.782544 1.409164 -0.111565 71 6 0 -5.962418 -0.552755 -1.539538 72 1 0 -4.524954 -2.146304 -1.219159 73 6 0 -6.411985 0.711884 -1.136704 74 1 0 -6.128217 2.390381 0.190693 75 1 0 -6.471321 -1.064682 -2.347156 76 1 0 -7.266226 1.153351 -1.635118 R = CN; TS(S) E = -2846.327150, ZPE = 0.574113, TC = 0.617426, S = 261.140, imag. freq. = -382 cm–1 1 7 0 -0.795710 2.288659 -0.265824 2 6 0 -2.094296 1.958756 -0.078231 3 16 0 -3.288019 3.066370 0.334264 4 7 0 -2.280408 0.613745 -0.244702 5 1 0 -1.436164 0.059142 -0.083238 6 1 0 -0.167497 1.571588 -0.642768 7 1 0 2.708791 1.793237 1.088290 8 7 0 3.438898 1.213329 0.664922 9 6 0 3.639974 1.097744 -0.638439 10 6 0 4.507773 -0.003223 -0.883035 11 1 0 3.112363 1.725337 -1.341794 12 1 0 5.043323 -0.123319 -1.813287 13 8 0 0.275842 -0.407592 0.755721 14 7 0 1.145222 -0.480135 -0.171719 15 8 0 1.063313 0.315857 -1.147200 16 6 0 2.139894 -1.377817 -0.107120 17 1 0 2.146058 -1.980009 0.785347 18 8 0 1.041867 2.155983 1.788373 19 1 0 0.443720 1.425637 1.537290 20 6 0 -0.168889 3.514500 0.138620 21 6 0 0.461021 3.424286 1.572704 22 1 0 -0.899553 4.327149 0.110661 23 6 0 1.049511 3.834851 -0.698597 24 6 0 1.616945 4.442909 1.534829 25 6 0 2.067867 4.355159 0.095627 26 6 0 1.215395 3.664318 -2.065167 27 1 0 1.247081 5.445739 1.765077

467

28 1 0 2.381039 4.181093 2.268617 29 6 0 3.283948 4.715442 -0.469022 30 1 0 0.418878 3.246658 -2.670857 31 6 0 2.433196 4.033767 -2.635214 32 1 0 4.085327 5.109669 0.145104 33 6 0 3.457487 4.552035 -1.843161 34 1 0 2.588240 3.909586 -3.700159 35 1 0 4.401348 4.824349 -2.299920 36 6 0 -3.481069 -0.106015 -0.191544 37 6 0 -3.461150 -1.350395 0.441664 38 6 0 -4.655500 0.339110 -0.793572 39 6 0 -4.610804 -2.123402 0.483353 40 1 0 -2.545651 -1.700014 0.906117 41 6 0 -5.798230 -0.448174 -0.722229 42 1 0 -4.673845 1.284479 -1.317424 43 6 0 -5.798221 -1.681005 -0.087155 44 6 0 -4.559935 -3.482823 1.117266 45 6 0 -7.054925 0.085372 -1.346981 46 1 0 -6.696004 -2.282657 -0.039777 47 9 0 -3.641801 -3.551035 2.089602 48 9 0 -5.737767 -3.829754 1.650831 49 9 0 -4.246146 -4.432957 0.221703 50 9 0 -7.530618 1.142697 -0.672888 51 9 0 -8.031240 -0.828604 -1.386608 52 9 0 -6.843742 0.498575 -2.605790 53 6 0 3.090186 -1.425500 -1.162535 54 1 0 2.731130 -0.997953 -2.092274 55 6 0 3.941371 -2.626315 -1.336570 56 6 0 4.177643 -3.540291 -0.305281 57 6 0 4.540943 -2.840986 -2.582667 58 6 0 4.991169 -4.646761 -0.521792 59 1 0 3.735538 -3.394226 0.672815 60 6 0 5.357458 -3.941873 -2.796222 61 1 0 4.361554 -2.135378 -3.387744 62 6 0 5.585387 -4.848269 -1.763064 63 1 0 5.163653 -5.350139 0.283665 64 1 0 5.812748 -4.095868 -3.767008 65 1 0 6.221693 -5.709456 -1.927549 66 6 0 4.265603 0.328440 1.373161 67 6 0 5.023406 -0.379837 0.431377 68 6 0 4.388946 0.140273 2.742724 69 6 0 5.962985 -1.310908 0.867237 70 6 0 5.332284 -0.791270 3.159020 71 1 0 3.780734 0.693725 3.447044 72 6 0 6.113453 -1.499633 2.236432 73 1 0 6.559454 -1.871479 0.157100 74 1 0 5.470113 -0.968243 4.218498 75 1 0 6.846362 -2.209280 2.600451

468

76 6 0 -0.504080 3.715000 2.652852 77 7 0 -1.221921 3.942178 3.519440 R = CN; TS(R) E = -2846.323743, ZPE = 0.574707, TC = 0.618082, S = 260.941, imag. freq. = -402 cm–1 1 7 0 0.637117 -2.463913 -0.060789 2 6 0 1.940269 -2.113295 0.052575 3 16 0 3.093380 -3.067334 0.818956 4 7 0 2.185180 -0.900566 -0.516704 5 1 0 1.353456 -0.378604 -0.799502 6 1 0 0.022017 -1.797873 -0.534699 7 1 0 -2.827719 -1.718811 0.906155 8 7 0 -3.361830 -0.852624 0.927741 9 6 0 -3.146924 0.087932 1.833993 10 1 0 -2.414180 -0.051311 2.612864 11 8 0 -1.093179 -2.029540 2.037347 12 1 0 -0.483967 -1.363969 1.666780 13 6 0 0.014099 -3.610629 0.540493 14 6 0 -0.551813 -3.327076 1.976729 15 1 0 0.729695 -4.436119 0.582934 16 6 0 -1.249389 -4.000300 -0.197145 17 6 0 -1.733589 -4.308948 2.114741 18 6 0 -2.243849 -4.390332 0.697224 19 6 0 -1.477249 -3.982790 -1.565030 20 1 0 -1.380190 -5.284455 2.459604 21 1 0 -2.458046 -3.926832 2.835160 22 6 0 -3.491859 -4.781744 0.232544 23 1 0 -0.701372 -3.662745 -2.251642 24 6 0 -2.728505 -4.381819 -2.033749 25 1 0 -4.272309 -5.080036 0.923018 26 6 0 -3.724065 -4.779885 -1.143175 27 1 0 -2.929851 -4.377026 -3.098086 28 1 0 -4.693022 -5.082346 -1.522653 29 6 0 3.374305 -0.152937 -0.424948 30 6 0 3.286102 1.162999 0.013010 31 6 0 4.609123 -0.676065 -0.811069 32 6 0 4.430458 1.953127 0.064074 33 1 0 2.324253 1.559044 0.322484 34 6 0 5.737040 0.124753 -0.733943 35 1 0 4.674703 -1.690578 -1.177397 36 6 0 5.666195 1.445253 -0.298567 37 6 0 4.288117 3.371460 0.533108 38 6 0 7.077427 -0.445085 -1.097117 39 1 0 6.554436 2.062158 -0.257348 40 9 0 5.456343 4.021196 0.552532 41 9 0 3.456297 4.068893 -0.256085 42 9 0 3.776172 3.432095 1.771780

469

43 9 0 7.861397 0.468002 -1.687856 44 9 0 6.975501 -1.485791 -1.932309 45 9 0 7.740028 -0.877781 -0.013500 46 6 0 -3.921566 1.236451 1.517127 47 1 0 -4.153661 1.992540 2.253085 48 6 0 -2.508892 2.242984 0.500809 49 6 0 -1.989494 1.432190 -0.542156 50 1 0 -1.838261 2.359173 1.345817 51 7 0 -1.000142 0.562054 -0.288605 52 1 0 -2.333094 1.425291 -1.562214 53 8 0 -0.538366 -0.145787 -1.237437 54 8 0 -0.517303 0.435036 0.870289 55 6 0 -3.259979 3.473727 0.146748 56 6 0 -3.329556 4.511059 1.082410 57 6 0 -3.901573 3.628722 -1.085904 58 6 0 -4.018983 5.680449 0.792553 59 1 0 -2.834726 4.397227 2.041626 60 6 0 -4.589847 4.801012 -1.376045 61 1 0 -3.874811 2.835674 -1.822881 62 6 0 -4.651985 5.827381 -0.439411 63 1 0 -4.060733 6.477787 1.524455 64 1 0 -5.079015 4.910865 -2.336354 65 1 0 -5.189410 6.739583 -0.668676 66 6 0 -4.388373 -0.470611 0.051536 67 6 0 -4.826433 0.798815 0.455867 68 6 0 -4.942658 -1.161134 -1.017104 69 6 0 -5.881603 1.405885 -0.220162 70 6 0 -5.991980 -0.536810 -1.680827 71 1 0 -4.572723 -2.135726 -1.312569 72 6 0 -6.460442 0.722654 -1.283625 73 1 0 -6.242183 2.382693 0.078799 74 1 0 -6.462251 -1.038152 -2.517779 75 1 0 -7.290113 1.170813 -1.816427 76 6 0 0.427737 -3.517630 3.067191 77 7 0 1.129422 -3.675658 3.961974 R = t-Bu; TS(S) E = -2911.316965, ZPE = 0.688360, TC = 0.735276, S = 275.960, imag. freq. = -387 cm–1

1 7 0 -0.781213 2.283061 0.054366 2 6 0 -2.090646 1.981818 0.032380 3 16 0 -3.328851 3.117583 0.156730 4 7 0 -2.270293 0.625835 -0.053043 5 1 0 -1.451731 0.080259 0.225710 6 1 0 -0.138687 1.549515 -0.257940 7 1 0 2.742341 1.826273 1.047324 8 7 0 3.453866 1.246425 0.578640 9 6 0 3.524237 1.060940 -0.729574

470

10 6 0 4.385449 -0.039309 -1.004018 11 1 0 2.915061 1.642562 -1.406380 12 1 0 4.825651 -0.204167 -1.976816 13 8 0 0.308145 -0.444726 1.048766 14 7 0 1.099217 -0.536105 0.058133 15 8 0 0.917705 0.216116 -0.937838 16 6 0 2.119418 -1.410198 0.072263 17 1 0 2.211468 -1.978566 0.981920 18 8 0 1.243005 2.193321 1.891720 19 1 0 0.618347 1.454366 1.795589 20 6 0 -0.159569 3.529841 0.423899 21 6 0 0.579967 3.460731 1.812385 22 1 0 -0.917301 4.315322 0.426800 23 6 0 0.967884 3.867676 -0.527520 24 6 0 1.737225 4.469555 1.639536 25 6 0 2.053118 4.393695 0.166652 26 6 0 1.012628 3.679928 -1.901810 27 1 0 1.419957 5.480233 1.910349 28 1 0 2.580572 4.201605 2.279254 29 6 0 3.213773 4.744486 -0.511259 30 1 0 0.165937 3.250570 -2.426852 31 6 0 2.174082 4.040254 -2.585117 32 1 0 4.069640 5.141115 0.023627 33 6 0 3.265627 4.565332 -1.893829 34 1 0 2.232843 3.901918 -3.658180 35 1 0 4.166059 4.828956 -2.435991 36 6 0 -3.459491 -0.101452 -0.169986 37 6 0 -3.525297 -1.330052 0.494408 38 6 0 -4.534244 0.308553 -0.955849 39 6 0 -4.658582 -2.117768 0.384175 40 1 0 -2.687901 -1.654612 1.101896 41 6 0 -5.665948 -0.495281 -1.036197 42 1 0 -4.486121 1.239853 -1.502031 43 6 0 -5.751044 -1.709190 -0.372885 44 6 0 -4.699809 -3.458104 1.057606 45 6 0 -6.815482 0.000468 -1.864930 46 1 0 -6.640117 -2.321792 -0.441232 47 9 0 -3.865942 -3.526115 2.102680 48 9 0 -5.927870 -3.754059 1.503285 49 9 0 -4.348425 -4.443422 0.215364 50 9 0 -7.379992 1.090886 -1.324240 51 9 0 -7.779865 -0.917244 -1.999190 52 9 0 -6.420859 0.347792 -3.099460 53 6 0 2.970893 -1.494471 -1.061581 54 1 0 2.522029 -1.123242 -1.976454 55 6 0 3.821326 -2.694578 -1.246575 56 6 0 4.196685 -3.520525 -0.182660 57 6 0 4.270121 -3.003813 -2.534772

471

58 6 0 4.993156 -4.637246 -0.408246 59 1 0 3.879176 -3.293090 0.827660 60 6 0 5.069842 -4.115555 -2.758696 61 1 0 3.983971 -2.366380 -3.365247 62 6 0 5.432625 -4.936674 -1.693544 63 1 0 5.273873 -5.270971 0.424244 64 1 0 5.405963 -4.345070 -3.762467 65 1 0 6.054444 -5.806728 -1.866733 66 6 0 4.366789 0.414787 1.242084 67 6 0 5.041409 -0.333032 0.267559 68 6 0 4.634395 0.307056 2.599934 69 6 0 6.045252 -1.217360 0.655321 70 6 0 5.638162 -0.580417 2.968054 71 1 0 4.088171 0.889109 3.331679 72 6 0 6.339525 -1.324494 2.009856 73 1 0 6.582474 -1.804300 -0.080280 74 1 0 5.887537 -0.693711 4.015811 75 1 0 7.124735 -1.996558 2.333756 76 6 0 -0.282431 3.678673 3.084633 77 6 0 -1.171811 4.922074 2.956684 78 6 0 -1.177223 2.458846 3.355754 79 6 0 0.657234 3.853339 4.287369 80 1 0 -1.976270 4.769466 2.233927 81 1 0 -1.633335 5.131548 3.925106 82 1 0 -0.603725 5.809407 2.665154 83 1 0 -0.585617 1.562849 3.560976 84 1 0 -1.784974 2.655796 4.242447 85 1 0 -1.863447 2.253877 2.532609 86 1 0 0.072981 3.864152 5.210681 87 1 0 1.371762 3.028916 4.343434 88 1 0 1.211373 4.793606 4.233501 R = t-Bu; TS(R) E = -2911.312875, ZPE = 0.688527, TC = 0.735608, S = 275.773, imag. freq. = -407 cm–1 1 7 0 0.733675 -2.242283 0.345125 2 6 0 2.050366 -2.033968 0.160039 3 16 0 3.238510 -3.195241 0.459379 4 7 0 2.306932 -0.759116 -0.257365 5 1 0 1.499785 -0.132149 -0.265085 6 1 0 0.112784 -1.486948 0.044435 7 1 0 -2.809428 -1.693948 0.940232 8 7 0 -3.455301 -0.902693 0.882291 9 6 0 -3.571543 -0.037728 1.874634 10 1 0 -3.025113 -0.179753 2.794122 11 8 0 -1.357165 -2.062888 2.134992

472

12 1 0 -0.755790 -1.305435 2.042366 13 6 0 0.097915 -3.458244 0.795917 14 6 0 -0.656851 -3.307007 2.164012 15 1 0 0.860725 -4.235832 0.861348 16 6 0 -1.010865 -3.885122 -0.142207 17 6 0 -1.783715 -4.358771 2.056167 18 6 0 -2.085248 -4.399766 0.579013 19 6 0 -1.044598 -3.802891 -1.526163 20 1 0 -1.445093 -5.338802 2.402351 21 1 0 -2.640829 -4.063403 2.663858 22 6 0 -3.219919 -4.850168 -0.082994 23 1 0 -0.207650 -3.382473 -2.073743 24 6 0 -2.179075 -4.265834 -2.193176 25 1 0 -4.065817 -5.242607 0.470680 26 6 0 -3.256226 -4.785348 -1.476606 27 1 0 -2.227471 -4.213755 -3.274455 28 1 0 -4.135741 -5.131316 -2.007221 29 6 0 3.551289 -0.154750 -0.496548 30 6 0 3.737022 1.147744 -0.040012 31 6 0 4.567170 -0.778310 -1.224442 32 6 0 4.930023 1.812302 -0.298402 33 1 0 2.950267 1.633873 0.526475 34 6 0 5.755191 -0.100882 -1.451669 35 1 0 4.421917 -1.774862 -1.614854 36 6 0 5.957306 1.197172 -0.995530 37 6 0 5.075087 3.227078 0.180041 38 6 0 6.868541 -0.802627 -2.173897 39 1 0 6.887844 1.714516 -1.187317 40 9 0 6.337609 3.662224 0.100828 41 9 0 4.321389 4.072821 -0.540534 42 9 0 4.683893 3.362008 1.455662 43 9 0 7.651681 0.056943 -2.839973 44 9 0 6.412015 -1.697431 -3.059050 45 9 0 7.663902 -1.469582 -1.322862 46 6 0 -4.371692 1.062641 1.457416 47 1 0 -4.862008 1.716965 2.163309 48 6 0 -2.870644 2.273920 0.921892 49 6 0 -2.060186 1.636257 -0.053460 50 1 0 -2.414074 2.330849 1.904603 51 7 0 -1.072979 0.808020 0.326653 52 1 0 -2.190015 1.709096 -1.119655 53 8 0 -0.382905 0.226323 -0.567474 54 8 0 -0.824298 0.594709 1.541816 55 6 0 -3.636332 3.491348 0.547782 56 6 0 -4.013032 4.378544 1.561322 57 6 0 -3.994198 3.780577 -0.772138 58 6 0 -4.726668 5.531686 1.265962 59 1 0 -3.738571 4.159410 2.588323

473

60 6 0 -4.708923 4.936413 -1.067332 61 1 0 -3.722684 3.108876 -1.576835 62 6 0 -5.077672 5.812755 -0.052127 63 1 0 -5.005756 6.211503 2.061628 64 1 0 -4.976877 5.151544 -2.094759 65 1 0 -5.633620 6.712401 -0.286912 66 6 0 -4.274410 -0.533245 -0.191916 67 6 0 -4.935620 0.649009 0.172390 68 6 0 -4.465830 -1.172540 -1.408357 69 6 0 -5.846938 1.219295 -0.713940 70 6 0 -5.377691 -0.586968 -2.277712 71 1 0 -3.929340 -2.080606 -1.658413 72 6 0 -6.063201 0.585745 -1.933093 73 1 0 -6.376540 2.128780 -0.457320 74 1 0 -5.566537 -1.050180 -3.238394 75 1 0 -6.776509 1.004931 -2.632252 76 6 0 0.198907 -3.407648 3.454996 77 6 0 1.105920 -2.176238 3.606690 78 1 0 1.688817 -2.274505 4.526004 79 1 0 1.812211 -2.082811 2.780003 80 1 0 0.528918 -1.251040 3.688629 81 6 0 -0.748176 -3.461283 4.663455 82 1 0 -1.313968 -4.395778 4.689696 83 1 0 -0.169054 -3.397112 5.587929 84 1 0 -1.453536 -2.627756 4.640494 85 6 0 1.082653 -4.662089 3.454428 86 1 0 1.553274 -4.765966 4.435564 87 1 0 0.509848 -5.573957 3.268640 88 1 0 1.880163 -4.591785 2.711801 trans-β-nitrostyrene; E = -514.071841, ZPE = 0.137942, TC = 0.147926, S = 95.984, no imag. freqs. 1 6 0 -3.109513 -1.014650 0.000000 2 6 0 -1.739578 -1.246400 -0.000000 3 6 0 -0.836084 -0.178046 -0.000000 4 6 0 -1.332639 1.132678 -0.000000 5 6 0 -2.699282 1.361877 0.000000 6 6 0 -3.590987 0.289645 0.000000 7 1 0 -3.797850 -1.850651 0.000000 8 1 0 -1.360484 -2.262360 -0.000000 9 1 0 -0.652865 1.976205 -0.000000 10 1 0 -3.073669 2.378151 0.000000 11 1 0 -4.658399 0.474417 0.000000 12 6 0 0.593903 -0.483706 -0.000000 13 1 0 0.873168 -1.533094 -0.000000

474

14 6 0 1.584982 0.405535 -0.000000 15 1 0 1.519464 1.482166 -0.000000 16 7 0 2.965050 -0.050516 -0.000000 17 8 0 3.815145 0.819781 0.000000 18 8 0 3.206006 -1.241798 0.000000 indole; E = -363.759392, ZPE = 0.130696, TC = 0.137809, S = 78.586, no imag. freqs. 1 6 0 2.133334 -0.720502 -0.000003 2 6 0 2.159918 0.688051 -0.000003 3 6 0 0.990008 1.424686 -0.000002 4 6 0 -0.240989 0.749285 -0.000001 5 6 0 -0.242804 -0.667401 -0.000002 6 6 0 0.937977 -1.416040 -0.000002 7 1 0 1.019733 2.508465 -0.000002 8 1 0 3.067340 -1.269748 -0.000004 9 1 0 3.115577 1.198740 -0.000004 10 6 0 -1.615023 1.166430 -0.000004 11 1 0 -1.989711 2.177549 -0.000003 12 6 0 -2.372796 0.029990 -0.000004 13 7 0 -1.554375 -1.074528 -0.000004 14 1 0 -3.444808 -0.088840 -0.000004 15 1 0 -1.870595 -2.030735 -0.000003 16 1 0 0.915641 -2.499405 -0.000002 catalyst R = H; E = -1876.240818, ZPE = 0.304467, TC = 0.329398, S = 172.943, no imag. freqs. 1 7 0 -1.383217 2.178357 1.315714 2 6 0 -1.898069 1.905631 0.111715 3 16 0 -2.451284 3.087404 -0.968446 4 7 0 -1.942533 0.589054 -0.239198 5 1 0 -2.179293 0.415855 -1.206473 6 1 0 -1.026278 1.411518 1.872940 7 8 0 -3.940564 2.857698 2.058127 8 1 0 -4.035174 3.184305 1.154099 9 6 0 -1.518602 3.465514 1.987034 10 6 0 -2.912390 3.586504 2.687455 11 1 0 -1.366912 4.244434 1.241411 12 6 0 -0.561445 3.553384 3.149712 13 6 0 -2.691909 3.053580 4.109030 14 1 0 -3.157985 4.653601 2.731439 15 6 0 -1.229546 3.325141 4.352763

475

16 6 0 0.805913 3.796395 3.117514 17 1 0 -3.350106 3.525411 4.839288 18 1 0 -2.892295 1.976974 4.125146 19 6 0 -0.528956 3.352192 5.552870 20 1 0 1.313939 3.971130 2.175486 21 6 0 1.506620 3.818528 4.320393 22 1 0 -1.038809 3.184306 6.494830 23 6 0 0.841614 3.599666 5.527159 24 1 0 2.572266 4.013073 4.321455 25 1 0 1.398915 3.626029 6.456182 26 6 0 -2.026870 -0.505614 0.655168 27 6 0 -1.346998 -1.680088 0.357380 28 6 0 -2.832014 -0.428958 1.796127 29 6 0 -1.475396 -2.778352 1.201192 30 1 0 -0.717552 -1.728628 -0.523539 31 6 0 -2.924298 -1.531251 2.630288 32 1 0 -3.380398 0.484402 2.013368 33 6 0 -2.252610 -2.716792 2.346162 34 6 0 -0.758246 -4.046722 0.834989 35 6 0 -3.833941 -1.484255 3.825271 36 1 0 -2.332086 -3.568816 3.008921 37 9 0 -0.729659 -4.921586 1.844762 38 9 0 -1.346624 -4.657976 -0.203855 39 9 0 0.509362 -3.808420 0.471630 40 9 0 -3.344377 -2.192277 4.850028 41 9 0 -5.040568 -1.994940 3.541289 42 9 0 -4.032786 -0.232338 4.257589 catalyst R = CN; E = -1968.475223, ZPE = 0.302513, TC = 0.329245, S = 183.225, no imag. freqs. 1 7 0 -1.483843 2.155646 1.336365 2 6 0 -2.003036 1.896009 0.125526 3 16 0 -2.543936 3.101405 -0.932612 4 7 0 -2.073438 0.587341 -0.230709 5 1 0 -2.339232 0.419683 -1.191691 6 1 0 -1.120440 1.389982 1.890902 7 8 0 -3.994122 3.060081 2.023210 8 1 0 -4.002679 3.291059 1.081144 9 6 0 -1.514008 3.461914 1.965537 10 6 0 -2.921964 3.713544 2.637511 11 1 0 -1.293216 4.214156 1.208947 12 6 0 -0.581489 3.503123 3.149913 13 6 0 -2.761336 3.201166 4.084596 14 6 0 -1.285489 3.356172 4.343390 15 6 0 0.800503 3.638864 3.136536

476

16 1 0 -3.393612 3.741424 4.788930 17 1 0 -3.059923 2.148436 4.098050 18 6 0 -0.608963 3.353300 5.556365 19 1 0 1.336164 3.755437 2.201287 20 6 0 1.477762 3.632549 4.352411 21 1 0 -1.147588 3.248694 6.490982 22 6 0 0.776852 3.491959 5.550312 23 1 0 2.554760 3.745778 4.370131 24 1 0 1.318184 3.496410 6.488783 25 6 0 -2.086274 -0.517265 0.657366 26 6 0 -1.366782 -1.662323 0.339194 27 6 0 -2.856411 -0.472673 1.821694 28 6 0 -1.420857 -2.760466 1.190868 29 1 0 -0.763974 -1.687674 -0.561128 30 6 0 -2.870198 -1.569825 2.667783 31 1 0 -3.437863 0.414758 2.053102 32 6 0 -2.158462 -2.725858 2.363962 33 6 0 -0.662831 -3.999581 0.805088 34 6 0 -3.732965 -1.534287 3.897846 35 1 0 -2.175763 -3.577477 3.031537 36 9 0 -0.574646 -4.871405 1.813659 37 9 0 -1.252347 -4.633008 -0.218944 38 9 0 0.584354 -3.709685 0.410904 39 9 0 -3.230975 -2.288783 4.880914 40 9 0 -4.967351 -1.989257 3.644777 41 9 0 -3.867879 -0.287956 4.373380 42 6 0 -3.139723 5.181555 2.654596 43 7 0 -3.303137 6.318202 2.655647 catalyst R = t-Bu; E = -2033.462768, ZPE = 0.416725, TC = 0.446971, S = 195.674, no imag. freqs. 1 7 0 -1.495126 2.164655 1.261396 2 6 0 -2.092365 1.856874 0.105908 3 16 0 -2.702625 3.004365 -0.975973 4 7 0 -2.173383 0.528866 -0.194584 5 1 0 -2.464278 0.325833 -1.140840 6 1 0 -1.100522 1.409714 1.809450 7 8 0 -3.917935 2.829005 2.233319 8 1 0 -4.097770 3.096446 1.322317 9 6 0 -1.540144 3.468852 1.915309 10 6 0 -2.879276 3.647982 2.744481 11 1 0 -1.414056 4.230944 1.147216 12 6 0 -0.463066 3.501487 2.970101 13 6 0 -2.501340 3.089787 4.138435 14 6 0 -1.008710 3.266398 4.228537 15 6 0 0.900347 3.699335 2.798027

477

16 1 0 -3.031927 3.575923 4.956595 17 1 0 -2.765618 2.028335 4.168740 18 6 0 -0.187612 3.236903 5.349435 19 1 0 1.314135 3.880380 1.811858 20 6 0 1.723180 3.671147 3.921639 21 1 0 -0.604437 3.065698 6.335778 22 6 0 1.180824 3.442045 5.186253 23 1 0 2.788924 3.833574 3.814633 24 1 0 1.831848 3.428363 6.052529 25 6 0 -2.156613 -0.544008 0.727326 26 6 0 -1.496758 -1.720072 0.388022 27 6 0 -2.838314 -0.448377 1.943769 28 6 0 -1.522692 -2.797941 1.265289 29 1 0 -0.959579 -1.784464 -0.551078 30 6 0 -2.829228 -1.531686 2.809009 31 1 0 -3.370858 0.464871 2.197624 32 6 0 -2.178403 -2.717061 2.483913 33 6 0 -0.834284 -4.069746 0.857922 34 6 0 -3.609055 -1.451899 4.090675 35 1 0 -2.178642 -3.554301 3.169516 36 9 0 -0.636576 -4.889867 1.894720 37 9 0 -1.552567 -4.746129 -0.050740 38 9 0 0.359717 -3.826869 0.301041 39 9 0 -3.075162 -2.217803 5.049106 40 9 0 -4.874227 -1.862222 3.921829 41 9 0 -3.668360 -0.199154 4.563158 42 6 0 -3.344883 5.141828 2.789731 43 6 0 -4.578977 5.271625 3.697280 44 6 0 -2.241558 6.065467 3.323839 45 6 0 -3.753738 5.625335 1.389042 46 1 0 -5.331833 4.525199 3.438158 47 1 0 -4.330524 5.164487 4.754558 48 1 0 -5.019909 6.263284 3.568111 49 1 0 -1.364123 6.084761 2.672072 50 1 0 -2.632287 7.084473 3.385084 51 1 0 -1.915297 5.771362 4.324132 52 1 0 -4.030273 6.680780 1.445861 53 1 0 -2.954689 5.527525 0.652973 54 1 0 -4.627828 5.085877 1.013590 E = M06-2X/6-311G(d,p) electronic energy using the PCM solvation model for DCM, ZPE = zero point energy, and TC = thermal correction to the enthalpy all of which are in Hartrees; S = entropy in cal mol–1 K–1.

478

References in Appendix for Chapter 5






479


NMR Spectra 1H NMR in CDCl3 for 6.5

NMR solvent

benzene

H2O

480


NMR solvent

H2O

481


NMR solvent

482


NMR solvent

483


NMR solvent

H2O

MeOH

484


NMR solvent

485

H2O

1H NMR in CD3CN for 6.14

NMR solvent

486

13C NMR in CD3CN for 6.14

NMR solvent NMR solvent

487

1H NMR in d6-DMSO for 6.20

NMR solvent

488

13C NMR in d6-DMSO for 6.20

NMR solvent

489


NMR solvent

490


NMR solvent

491


Fluorobenzene

492


NMR solvent

pentane H2O

493


NMR solvent

494


Fluorobenzene

495


NMR solvent

496


NMR solvent

497


Fluorobenzene

498


NMR solvent

H2O

CH3CN

acetone

499


NMR solvent

500


Fluorobenzene

Charge-Enhanced Brønsted Acids: Catalyst Designs and ...

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